The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis
2021; Elsevier BV; Volume: 297; Issue: 3 Linguagem: Inglês
10.1016/j.jbc.2021.101032
ISSN1083-351X
AutoresKazuhiko Igarashi, Hironari Nishizawa, Yuriko Saiki, Mitsuyo Matsumoto,
Tópico(s)RNA modifications and cancer
ResumoThe progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT. The progression of cancer involves not only the gradual evolution of cells by mutations in DNA but also alterations in the gene expression induced by those mutations and input from the surrounding microenvironment. Such alterations contribute to cancer cells' abilities to reprogram metabolic pathways and undergo epithelial-to-mesenchymal transition (EMT), which facilitate the survival of cancer cells and their metastasis to other organs. Recently, BTB and CNC homology 1 (BACH1), a heme-regulated transcription factor that represses genes involved in iron and heme metabolism in normal cells, was shown to shape the metabolism and metastatic potential of cancer cells. The growing list of BACH1 target genes in cancer cells reveals that BACH1 promotes metastasis by regulating various sets of genes beyond iron metabolism. BACH1 represses the expression of genes that mediate cell–cell adhesion and oxidative phosphorylation but activates the expression of genes required for glycolysis, cell motility, and matrix protein degradation. Furthermore, BACH1 represses FOXA1 gene encoding an activator of epithelial genes and activates SNAI2 encoding a repressor of epithelial genes, forming a feedforward loop of EMT. By synthesizing these observations, we propose a "two-faced BACH1 model", which accounts for the dynamic switching between metastasis and stress resistance along with cancer progression. We discuss here the possibility that BACH1-mediated promotion of cancer also brings increased sensitivity to iron-dependent cell death (ferroptosis) through crosstalk of BACH1 target genes, imposing programmed vulnerability upon cancer cells. We also discuss the future directions of this field, including the dynamics and plasticity of EMT. Cancer cells are suggested to reflect an evolutionary process in which genetic mutations modify cells, giving rise to variations. The ensuing struggle for existence (1Darwin J. The Origin of Species by Means of Natural Selection. Project Guttenberg, 1860Google Scholar) of these cells within the body selects for improved and/or adapted forms of cancer cells in terms of so-called cancer hallmarks (2Hanahan D. Weinberg R.A. Hallmarks of cancer: The next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (35863) Google Scholar) including proliferation, invasion, and metastasis, as well as stress resistance. Some cancer cells eventually dominate not only competing fellow cancer cells but also the surrounding normal cells. During the struggle for existence, cancer cells alter their properties and functions by not only genetic mutations but also changes in their gene expression in response to their microenvironment and therapeutic interventions (3Makohon-Moore A. Iacobuzio-Donahue C.A. Pancreatic cancer biology and genetics from an evolutionary perspective.Nat. Rev. Cancer. 2016; 16: 553-565Crossref PubMed Scopus (197) Google Scholar). The modulability of gene expression, including epigenetic alterations, may be another foundation of cancer cell evolution, as heterogeneity thus formed allows for the selection of better-fitted cells among genetically similar cells. Therefore, some of the sinister properties of cancer cells such as metastasis, which underlie the difficulties in treating patients with cancer, may not be entirely attributable to genetic mutations alone. Metastasis depends on alterations in the gene expression and involves multiple steps of local invasion, intravasation, extravasation, and reproliferation (4Valastyan S. Weinberg R.A. Tumor metastasis: Molecular insights and evolving paradigms.Cell. 2011; 147: 275-292Abstract Full Text Full Text PDF PubMed Scopus (2260) Google Scholar). Epithelial-to-mesenchymal transition (EMT) can explain many of the alterations incurred by cancer cells during metastasis, which reduces the cell adhesion capability and increases mobility and invasiveness (5Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer.Nat. Rev. Mol. Cell Biol. 2019; 20: 69-84Crossref PubMed Scopus (787) Google Scholar). Transcription factors known to regulate EMT include ZEB1, ZEB2, SNAI1 (SNAIL), SNAI2 (SLUG), and TWIST1 and have been suggested to promote cancer progression, including metastasis (5Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer.Nat. Rev. Mol. Cell Biol. 2019; 20: 69-84Crossref PubMed Scopus (787) Google Scholar, 6Puisieux A. Brabletz T. Caramel J. Oncogenic roles of EMT-inducing transcription factors.Nat. Cell Biol. 2014; 16: 488-494Crossref PubMed Scopus (581) Google Scholar, 7Nieto M.A. Huang R.Y. Jackson R.A. Thiery J.P. Emt: 2016.Cell. 2016; 166: 21-45Abstract Full Text Full Text PDF PubMed Google Scholar, 8Stemmler M.P. Eccles R.L. Brabletz S. Brabletz T. Non-redundant functions of EMT transcription factors.Nat. Cell Biol. 2019; 21: 102-112Crossref PubMed Scopus (155) Google Scholar). However, the direct target genes of these EMT-related transcription factors, shared among them or unique to one of them, largely remain elusive (8Stemmler M.P. Eccles R.L. Brabletz S. Brabletz T. Non-redundant functions of EMT transcription factors.Nat. Cell Biol. 2019; 21: 102-112Crossref PubMed Scopus (155) Google Scholar). Transcription factors play critical roles in the survival of cancer cells, which are placed under stress derived from their hostile microenvironments of low oxygen, low nutrients, including glucose, and attack by immune cells. Changes in the signaling and metabolism within cancer cells impose endogenous stress. The survival of these cells despite such stress is dependent on their altered gene expression, choreographed by transcription factors. Hypoxia-responsive factor (HIF1A) induces neoangiogenesis (9Ivan M. Kaelin Jr., W.G. The EGLN-HIF O(2)-sensing system: Multiple inputs and feedbacks.Mol. Cell. 2017; 66: 772-779Abstract Full Text Full Text PDF PubMed Google Scholar, 10Semenza G.L. Pharmacologic targeting of hypoxia-inducible factors.Annu. Rev. Pharmacol. Toxicol. 2019; 59: 379-403Crossref PubMed Scopus (71) Google Scholar) and reprogramming of glucose metabolism from oxidative phosphorylation to the combination of glycolysis and oxidative phosphorylation (aerobic glycolysis) (9Ivan M. Kaelin Jr., W.G. The EGLN-HIF O(2)-sensing system: Multiple inputs and feedbacks.Mol. Cell. 2017; 66: 772-779Abstract Full Text Full Text PDF PubMed Google Scholar, 11Luengo A. Li Z. Gui D.Y. Sullivan L.B. Zagorulya M. Do B.T. Ferreira R. Naamati A. Ali A. Lewis C.A. Thomas C.J. Spranger S. Matheson N.J. Vander Heiden M.G. Increased demand for NAD(+) relative to ATP drives aerobic glycolysis.Mol. Cell. 2021; 81: 691-707.e6Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Heat shock factor HSF1 maintains protein homeostasis (12Fujimoto M. Takii R. Takaki E. Katiyar A. Nakato R. Shirahige K. Nakai A. The HSF1-PARP13-PARP1 complex facilitates DNA repair and promotes mammary tumorigenesis.Nat. Commun. 2017; 8: 1638Crossref PubMed Scopus (9) Google Scholar). Activator protein-1 (AP-1) transcription factors, such as JUN and FOS, which are characterized by the presence of basic leucine zipper (bZip) DNA-binding domain, are the downstream effector molecules of the mitogen-activated protein kinase and extracellular signal-regulated kinase signaling cascades and promote stress resistance against inflammation and oxidative stress (13Bejjani F. Evanno E. Zibara K. Piechaczyk M. Jariel-Encontre I. The AP-1 transcriptional complex: Local switch or remote command?.Biochim. Biophys. Acta Rev. Cancer. 2019; 1872: 11-23Crossref PubMed Scopus (40) Google Scholar). NF-E2-related factor 2 (NFE2L2), another transcription factor with a bZip domain, supports tumor cell proliferation in part by activating oxidative stress response (14Kitamura H. Motohashi H. NRF2 addiction in cancer cells.Cancer Sci. 2018; 109: 900-911Crossref PubMed Scopus (102) Google Scholar, 15Yamamoto M. Kensler T.W. Motohashi H. The KEAP1-NRF2 system: A thiol-based sensor-effector apparatus for maintaining redox homeostasis.Physiol. Rev. 2018; 98: 1169-1203Crossref PubMed Scopus (407) Google Scholar, 16Taguchi K. Yamamoto M. The KEAP1-NRF2 system as a molecular target of cancer treatment.Cancers (Basel). 2020; 13Crossref PubMed Scopus (5) Google Scholar). The focus of this review is BTB and CNC homology 1 (BACH1) (17Oyake T. Itoh K. Motohashi H. Hayashi N. Hoshino H. Nishizawa M. Yamamoto M. Igarashi K. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site.Mol. Cell. Biol. 1996; 16: 6083-6095Crossref PubMed Scopus (477) Google Scholar, 18Kanezaki R. Toki T. Yokoyama M. Yomogida K. Sugiyama K. Yamamoto M. Igarashi K. Ito E. Transcription factor BACH1 is recruited to the nucleus by its novel alternative spliced isoform.J. Biol. Chem. 2001; 276: 7278-7284Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), which regulates iron- and heme-related genes in normal cells (19Igarashi K. Watanabe-Matsui M. Wearing red for signaling: The heme-bach axis in heme metabolism, oxidative stress response and iron immunology.Tohoku J. Exp. Med. 2014; 232: 229-253Crossref PubMed Scopus (68) Google Scholar, 20Kobayashi M. Kato H. Hada H. Itoh-Nakadai A. Fujiwara T. Muto A. Inoguchi Y. Ichiyanagi K. Hojo W. Tomosugi N. Sasaki H. Harigae H. Igarashi K. Iron-heme-Bach1 axis is involved in erythroblast adaptation to iron deficiency.Haematologica. 2017; 102: 454-465Crossref PubMed Scopus (14) Google Scholar). Investigations on various types of human cancers have established that BACH1 promotes cancer progression via multiple mechanisms (Fig. 1, A and B). We first review the basic structure, function, and regulation of this transcription factor. We then summarize recent findings on the function of BACH1 in cancer cells and examine how the properties of cancer cells, including EMT, altered metabolism, metastasis, angiogenesis, and epigenetics, can be explained based on the established and/or putative BACH1 target genes. We propose a "two-faced BACH1 model" to integrate diverse functions of BACH1 in cancer cells. We additionally consider how other features of cancer cells, such as their dynamics and plasticity, and ferroptosis (iron-dependent cell death) may be shaped by BACH1. These findings make a compelling case that examining the roles of transcription factors is key to the global understanding of cancer biology. Among the human transcription factors, there are 61 transcription factors with a bZip DNA-binding domain, thus constituting the fourth most abundant family of transcription factors after the zinc finger, homeodomain, and basic helix–loop–helix protein families (21Lambert S.A. Jolma A. Campitelli L.F. Das P.K. Yin Y. Albu M. Chen X. Taipale J. Hughes T.R. Weirauch M.T. The human transcription factors.Cell. 2018; 172: 650-665Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar). The bZip family can be further classified into subfamilies according to their structural features. BACH1 and BACH2 are the only bZip factors with the combination of broad-complex, tramtrack, bric-a-brac (BTB) and bZip domains (17Oyake T. Itoh K. Motohashi H. Hayashi N. Hoshino H. Nishizawa M. Yamamoto M. Igarashi K. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site.Mol. Cell. Biol. 1996; 16: 6083-6095Crossref PubMed Scopus (477) Google Scholar) (Fig. 2A). However, their bZip domains are closely related to those of the cap'n'collar (CNC) subfamily, which is characterized by the presence of a short, evolutionarily conserved segment preceding the bZip domain. This segment was originally found in Drosophila transcription factor CNC (22Mohler J. Vani K. Leung S. Epstein A. Segmentally restricted, cephalic expression of a leucine zipper gene during Drosophila embryogenesis.Mech. Dev. 1991; 34: 3-9Crossref PubMed Scopus (107) Google Scholar), from which the etymology of the subfamily name is derived. It is required for DNA binding (23Bean T.L. Ney P.A. Multiple regions of p45 NF-E2 are required for beta-globin gene expression in erythroid cells.Nucleic Acids Res. 1997; 25: 2509-2515Crossref PubMed Scopus (0) Google Scholar) and is shared among BACH1, BACH2, NFE2 (NF-E2 p45), NFE2L1 (NRF1), NFE2L2 (NF-E2-related factor 2), which regulates oxidative stress response, and NFE2L3 (NRF3) (24Motohashi H. O'Connor T. Katsuoka F. Engel J.D. Yamamoto M. Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors.Gene. 2002; 294: 1-12Crossref PubMed Scopus (363) Google Scholar). The NFE2, NFE2L1, NFE2L2, and NFE2L3 genes are each linked to one or the other of the four clusters of HOX genes, which encode HOX family transcription factors important for the body plan in development. Because quadruplication of HOX clusters reflects two consecutive genome duplications during the evolution of vertebrates from deuterostomes (25Kuraku S. Meyer A. The evolution and maintenance of Hox gene clusters in vertebrates and the teleost-specific genome duplication.Int. J. Dev. Biol. 2009; 53: 765-773Crossref PubMed Scopus (0) Google Scholar), NFE2, NFE2L1, NFE2L2, and NFE2L3 may have adopted roles specific to vertebrate. In contrast, BACH1 and BACH2 are not linked to the HOX gene clusters, suggesting that the presumptive ancestor gene had first been separated into BACH and NFE2 type genes before or during the evolution of chordates, which possess a single Bach homolog (26Amoutzias G.D. Veron A.S. Weiner J. Robinson-Rechavi M. Bornberg-Bauer E. Oliver S.G. Robertson D.L. One billion years of bZIP transcription factor evolution: Conservation and change in dimerization and DNA-binding site specificity.Mol. Biol. Evol. 2007; 24: 827-835Crossref PubMed Scopus (107) Google Scholar). These factors form heterodimers with the small MAF oncoproteins (MAFF, MAFG, and MAFK) to bind to a DNA element referred to originally as an MAF recognition element (MARE) (27Kataoka K. Noda M. Nishizawa M. Maf nuclear oncoprotein recognizes sequences related to an AP-1 site and forms heterodimers with both Fos and Jun.Mol. Cell. Biol. 1994; 14: 700-712Crossref PubMed Google Scholar) and recently as CNC–sMAF–binding element (28Otsuki A. Suzuki M. Katsuoka F. Tsuchida K. Suda H. Morita M. Shimizu R. Yamamoto M. Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection.Free Radic. Biol. Med. 2016; 91: 45-57Crossref PubMed Scopus (38) Google Scholar, 29Otsuki A. Yamamoto M. Cis-element architecture of Nrf2-sMaf heterodimer binding sites and its relation to diseases.Arch. Pharm. Res. 2020; 43: 275-285Crossref PubMed Scopus (0) Google Scholar) (Fig. 2B). Because MARE embeds a motif for activator protein-1, MARE and its related motifs can be bound by AP-1 factors such as JUN and FOS (30Igarashi K. Kurosaki T. Roychoudhuri R. BACH transcription factors in innate and adaptive immunity.Nat. Rev. Immunol. 2017; 17: 437-450Crossref PubMed Scopus (46) Google Scholar). The BTB domain mediates homophilic protein interaction, and hence, transcription factors with the BTB domain may thus mediate long-range interaction of cis elements (31Igarashi K. Hoshino H. Muto A. Suwabe N. Nishikawa S. Nakauchi H. Yamamoto M. Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for beta-globin locus control region complex.J. Biol. Chem. 1998; 273: 11783-11790Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 32Yoshida C. Tokumasu F. Hohmura K.I. Bungert J. Hayashi N. Nagasawa T. Engel J.D. Yamamoto M. Takeyasu K. Igarashi K. Long range interaction of cis-DNA elements mediated by architectural transcription factor Bach1.Genes Cells. 1999; 4: 643-655Crossref PubMed Google Scholar). The BTB domain of the zinc finger protein BCL6 mediates interaction with corepressors as well (33Ahmad K.F. Melnick A. Lax S. Bouchard D. Liu J. Kiang C.L. Mayer S. Takahashi S. Licht J.D. Privé G.G. Mechanism of SMRT corepressor recruitment by the BCL6 BTB domain.Mol. Cell. 2003; 12: 1551-1564Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). The BTB domain of BACH1 is also bound by ubiquitin E3 ligase adaptor proteins (34Słabicki M. Yoon H. Koeppel J. Nitsch L. Roy Burman S.S. Di Genua C. Donovan K.A. Sperling A.S. Hunkeler M. Tsai J.M. Sharma R. Guirguis A. Zou C. Chudasama P. Gasser J.A. et al.Small-molecule-induced polymerization triggers degradation of BCL6.Nature. 2020; 588: 164-168Crossref PubMed Scopus (23) Google Scholar, 35Wang P. Song J. Ye D. CRL3s: The BTB-CUL3-RING E3 ubiquitin ligases.Adv. Exp. Med. Biol. 2020; 1217: 211-223Crossref PubMed Scopus (7) Google Scholar), and the BACH1 BTB domain directly binds to NANOG (36Niu C. Wang S. Guo J. Wei X. Jia M. Chen Z. Gong W. Qin Y. Wang X. Zhi X. Lu M. Chen S. Gu M. Zhang J. Han J.J. Lan F. Meng D. BACH1 recruits NANOG and histone H3 lysine 4 methyltransferase MLL/SET1 complexes to regulate enhancer-promoter activity and maintains pluripotency.Nucleic Acids Res. 2021; 49: 1972-1986Crossref PubMed Scopus (0) Google Scholar). BACH1 and BACH2 function as transcription repressors by recruiting corepressors NCOR1, NCOR2, and the histone deacetylases such as histone deacetylase 1 (HDAC1) and histone deacetylase 3 (37Muto A. Hoshino H. Madisen L. Yanai N. Obinata M. Karasuyama H. Hayashi N. Nakauchi H. Yamamoto M. Groudine M. Igarashi K. Identification of Bach2 as a B-cell-specific partner for small Maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer.EMBO J. 1998; 17: 5734-5743Crossref PubMed Scopus (150) Google Scholar, 38Dohi Y. Ikura T. Hoshikawa Y. Katoh Y. Ota K. Nakanome A. Muto A. Omura S. Ohta T. Ito A. Yoshida M. Noda T. Igarashi K. Bach1 inhibits oxidative stress-induced cellular senescence by impeding p53 function on chromatin.Nat. Struct. Mol. Biol. 2008; 15: 1246-1254Crossref PubMed Scopus (65) Google Scholar, 39Tanaka H. Muto A. Shima H. Katoh Y. Sax N. Tajima S. Brydun A. Ikura T. Yoshizawa N. Masai H. Hoshikawa Y. Noda T. Nio M. Ochiai K. Igarashi K. Epigenetic regulation of the Blimp-1 gene (Prdm1) in B cells involves Bach2 and histone deacetylase 3.J. Biol. Chem. 2016; 291: 6316-6330Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 40Jiang L. Yin M. Xu J. Jia M. Sun S. Wang X. Zhang J. Meng D. The transcription factor Bach1 suppresses the developmental angiogenesis of zebrafish.Oxid. Med. Cell Longev. 2017; 2017: 2143875Crossref PubMed Scopus (16) Google Scholar). Because their binding sites embed the AP-1 site, these transcription factors may compete with AP-1 factors to repress their shared target genes (Fig. 2B) (30Igarashi K. Kurosaki T. Roychoudhuri R. BACH transcription factors in innate and adaptive immunity.Nat. Rev. Immunol. 2017; 17: 437-450Crossref PubMed Scopus (46) Google Scholar). Note that while BACH target genes may also be regulated by AP-1 factors, AP-1 target genes are not necessarily regulated by BACH1 or BACH2, as the recognized sequences for the heterodimers of BACH1 or BACH2 with the small MAF proteins are longer than those of AP-1 factors (Fig. 2B). The antagonistic relationship between BACH2 and AP-1 is well established in the regulation of T cell activation and regulatory T cell differentiation (41Roychoudhuri R. Hirahara K. Mousavi K. Clever D. Klebanoff C.A. Bonelli M. Sciumè G. Zare H. Vahedi G. Dema B. Yu Z. Liu H. Takahashi H. Rao M. Muranski P. Crompton J.G. et al.BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.Nature. 2013; 498: 506-510Crossref PubMed Scopus (248) Google Scholar, 42Roychoudhuri R. Clever D. Li P. Wakabayashi Y. Quinn K.M. Klebanoff C.A. Ji Y. Sukumar M. Eil R.L. Yu Z. Spolski R. Palmer D.C. Pan J.H. Patel S.J. Macallan D.C. et al.BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.Nat. Immunol. 2016; 17: 851-860Crossref PubMed Google Scholar, 43Kuwahara M. Ise W. Ochi M. Suzuki J. Kometani K. Maruyama S. Izumoto M. Matsumoto A. Takemori N. Takemori A. Shinoda K. Nakayama T. Ohara O. Yasukawa M. Sawasaki T. et al.Bach2-Batf interactions control Th2-type immune response by regulating the IL-4 amplification loop.Nat. Commun. 2016; 7: 12596Crossref PubMed Scopus (43) Google Scholar). BACH1 and BACH2 are the only bZip factors known to be regulated by direct binding of heme, a prosthetic group involved in the transport of oxygen and electron (44Ogawa K. Sun J. Taketani S. Nakajima O. Nishitani C. Sassa S. Hayashi N. Yamamoto M. Shibahara S. Fujita H. Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.EMBO J. 2001; 20: 2835-2843Crossref PubMed Scopus (384) Google Scholar, 45Hira S. Tomita T. Matsui T. Igarashi K. Ikeda-Saito M. Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure.IUBMB Life. 2007; 59: 542-551Crossref PubMed Scopus (75) Google Scholar, 46Watanabe-Matsui M. Muto A. Matsui T. Itoh-Nakadai A. Nakajima O. Murayama K. Yamamoto M. Ikeda-Saito M. Igarashi K. Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.Blood. 2011; 117: 5438-5448Crossref PubMed Scopus (63) Google Scholar, 47Watanabe-Matsui M. Matsumoto T. Matsui T. Ikeda-Saito M. Muto A. Murayama K. Igarashi K. Heme binds to an intrinsically disordered region of Bach2 and alters its conformation.Arch. Biochem. Biophys. 2015; 565: 25-31Crossref PubMed Scopus (22) Google Scholar, 48Suenaga T. Watanabe-Matsui M. Uejima T. Shima H. Matsui T. Ikeda-Saito M. Shirouzu M. Igarashi K. Murayama K. Charge-state-distribution analysis of Bach2 intrinsically disordered heme binding region.J. Biochem. 2016; 160: 291-298Crossref PubMed Scopus (0) Google Scholar, 49Segawa K. Watanabe-Matsui M. Matsui T. Igarashi K. Murayama K. Functional heme binding to the intrinsically disordered C-terminal region of Bach1, a transcriptional repressor.Tohoku J. Exp. Med. 2019; 247: 153-159Crossref PubMed Scopus (0) Google Scholar, 50Segawa K. Watanabe-Matsui M. Tsuda K. Matsui T. Shirouzu M. Igarashi K. Murayama K. Biophysical characterization of heme binding to the intrinsically disordered region of Bach1.Eur. Biophys. J. 2019; 48: 361-369Crossref PubMed Scopus (0) Google Scholar). These factors, together with other heme binding proteins, suggest new roles of heme sensors and gas sensors (51Shimizu T. Lengalova A. Martínek V. Martínková M. Heme: Emergent roles of heme in signal transduction, functional regulation and as catalytic centres.Chem. Soc. Rev. 2019; 48: 5624-5657Crossref PubMed Google Scholar). Conventional heme proteins, such as globin, myoglobin, and cytochrome c, bind to heme via well-structured protein regions (52Gell D.A. Structure and function of haemoglobins.Blood Cells Mol. Dis. 2018; 70: 13-42Crossref PubMed Scopus (50) Google Scholar). In contrast, heme binds to BACH1 and BACH2 via cysteine–proline motifs embedded in an intrinsically disordered region (44Ogawa K. Sun J. Taketani S. Nakajima O. Nishitani C. Sassa S. Hayashi N. Yamamoto M. Shibahara S. Fujita H. Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.EMBO J. 2001; 20: 2835-2843Crossref PubMed Scopus (384) Google Scholar, 45Hira S. Tomita T. Matsui T. Igarashi K. Ikeda-Saito M. Bach1, a heme-dependent transcription factor, reveals presence of multiple heme binding sites with distinct coordination structure.IUBMB Life. 2007; 59: 542-551Crossref PubMed Scopus (75) Google Scholar, 46Watanabe-Matsui M. Muto A. Matsui T. Itoh-Nakadai A. Nakajima O. Murayama K. Yamamoto M. Ikeda-Saito M. Igarashi K. Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.Blood. 2011; 117: 5438-5448Crossref PubMed Scopus (63) Google Scholar, 47Watanabe-Matsui M. Matsumoto T. Matsui T. Ikeda-Saito M. Muto A. Murayama K. Igarashi K. Heme binds to an intrinsically disordered region of Bach2 and alters its conformation.Arch. Biochem. Biophys. 2015; 565: 25-31Crossref PubMed Scopus (22) Google Scholar, 48Suenaga T. Watanabe-Matsui M. Uejima T. Shima H. Matsui T. Ikeda-Saito M. Shirouzu M. Igarashi K. Murayama K. Charge-state-distribution analysis of Bach2 intrinsically disordered heme binding region.J. Biochem. 2016; 160: 291-298Crossref PubMed Scopus (0) Google Scholar, 49Segawa K. Watanabe-Matsui M. Matsui T. Igarashi K. Murayama K. Functional heme binding to the intrinsically disordered C-terminal region of Bach1, a transcriptional repressor.Tohoku J. Exp. Med. 2019; 247: 153-159Crossref PubMed Scopus (0) Google Scholar, 50Segawa K. Watanabe-Matsui M. Tsuda K. Matsui T. Shirouzu M. Igarashi K. Murayama K. Biophysical characterization of heme binding to the intrinsically disordered region of Bach1.Eur. Biophys. J. 2019; 48: 361-369Crossref PubMed Scopus (0) Google Scholar) (Fig. 2A). Heme inhibits their DNA-binding activity (44Ogawa K. Sun J. Taketani S. Nakajima O. Nishitani C. Sassa S. Hayashi N. Yamamoto M. Shibahara S. Fujita H. Igarashi K. Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1.EMBO J. 2001; 20: 2835-2843Crossref PubMed Scopus (384) Google Scholar, 46Watanabe-Matsui M. Muto A. Matsui T. Itoh-Nakadai A. Nakajima O. Murayama K. Yamamoto M. Ikeda-Saito M. Igarashi K. Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.Blood. 2011; 117: 5438-5448Crossref PubMed Scopus (63) Google Scholar, 53Sun J. Brand M. Zenke Y. Tashiro S. Groudine M. Igarashi K. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network.Proc. Natl. Acad. Sci. U. S. A. 2004; 101: 1461-1466Crossref PubMed Scopus (270) Google Scholar) and induces nuclear export (54Suzuki H. Tashiro S. Hira S. Sun J. Yamazaki C. Zenke Y. Ikeda-Saito M. Yoshida M. Igarashi K. Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1.EMBO J. 2004; 23: 2544-2553Crossref PubMed Scopus (153) Google Scholar, 55Suzuki H. Tashiro S. Sun J. Doi H. Satomi S. Igarashi K. Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene.J. Biol. Chem. 2003; 278: 49246-49253Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar), polyubiquitination, and subsequent degradation (46Watanabe-Matsui M. Muto A. Matsui T. Itoh-Nakadai A. Nakajima O. Murayama K. Yamamoto M. Ikeda-Saito M. Igarashi K. Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2.Blood. 2011; 117: 5438-5448Crossref PubMed Scopus (63) Google Scholar, 56Zenke-Kawasaki Y. Dohi Y. Katoh Y. Ikura T. Ikura M. Asahara T. Tokunaga F. Iwai K. Igarashi K. Heme induces ubiquitination and degradation of the transcription factor Bach1.Mol. Cell Biol. 2007; 27: 6962-6971Crossref PubMed Scopus (185) Google Scholar) (Fig. 2C). BACH1 represses target genes involved in the utilization or mobilization of iron, including HMOX1 for heme oxygenase-1 (HO-1) (57Sun J. Hoshino H. Takaku K. Nakajima O. Muto A. Suzuki H. Tashiro S. Takahashi S. Shibahara S. Alam J. Taketo M.M. Yamamoto M. Igarashi K. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene.EMBO J. 2002; 21: 5216-5224Crossref PubMed Scopus (460) Google Scholar), FTH1 and FTL for ferritin heavy- and light-chain subunits (58Hintze K.J. Katoh Y. Igarashi K. Theil E.C. Bach1 repression of ferritin and thioredoxin reductase1 is heme-sensitive in cells and in vitro and coordinates expression with heme oxygenase1, beta-globin, and NADP(H) quinone (oxido) reductase1.J. Biol. Chem. 2007; 282: 34365-34371Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar), and SLC40A1 for ferroporti
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