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Identification of the SOX2 Interactome by BioID Reveals EP300 as a Mediator of SOX2-dependent Squamous Differentiation and Lung Squamous Cell Carcinoma Growth

2017; Elsevier BV; Volume: 16; Issue: 10 Linguagem: Inglês

10.1074/mcp.m116.064451

ISSN

1535-9484

Autores

Bo Ram Kim, Étienne Coyaud, Estelle Laurent, Jonathan St‐Germain, Emily Van de Laar, Ming‐Sound Tsao, Brian Raught, Nadeem Moghal,

Tópico(s)

Peptidase Inhibition and Analysis

Resumo

Lung cancer is the leading cause of cancer mortality worldwide, with squamous cell carcinoma (SQCC) being the second most common form. SQCCs are thought to originate in bronchial basal cells through an injury response to smoking, which results in this stem cell population committing to hyperplastic squamous rather than mucinous and ciliated fates. Copy number gains in SOX2 in the region of 3q26–28 occur in 94% of SQCCs, and appear to act both early and late in disease progression by stabilizing the initial squamous injury response in stem cells and promoting growth of invasive carcinoma. Thus, anti-SOX2 targeting strategies could help treat early and/or advanced disease. Because SOX2 itself is not readily druggable, we sought to characterize SOX2 binding partners, with the hope of identifying new strategies to indirectly interfere with SOX2 activity. We now report the first use of proximity-dependent biotin labeling (BioID) to characterize the SOX2 interactome in vivo. We identified 82 high confidence SOX2-interacting partners. An interaction with the coactivator EP300 was subsequently validated in both basal cells and SQCCs, and we demonstrate that EP300 is necessary for SOX2 activity in basal cells, including for induction of the squamous fate. We also report that EP300 copy number gains are common in SQCCs and that growth of lung cancer cell lines with 3q gains, including SQCC cells, is dependent on EP300. Finally, we show that EP300 inhibitors can be combined with other targeted therapeutics to achieve more effective growth suppression. Our work supports the use of BioID to identify interacting protein partners of nondruggable oncoproteins such as SOX2, as an effective strategy to discover biologically relevant, druggable targets. Lung cancer is the leading cause of cancer mortality worldwide, with squamous cell carcinoma (SQCC) being the second most common form. SQCCs are thought to originate in bronchial basal cells through an injury response to smoking, which results in this stem cell population committing to hyperplastic squamous rather than mucinous and ciliated fates. Copy number gains in SOX2 in the region of 3q26–28 occur in 94% of SQCCs, and appear to act both early and late in disease progression by stabilizing the initial squamous injury response in stem cells and promoting growth of invasive carcinoma. Thus, anti-SOX2 targeting strategies could help treat early and/or advanced disease. Because SOX2 itself is not readily druggable, we sought to characterize SOX2 binding partners, with the hope of identifying new strategies to indirectly interfere with SOX2 activity. We now report the first use of proximity-dependent biotin labeling (BioID) to characterize the SOX2 interactome in vivo. We identified 82 high confidence SOX2-interacting partners. An interaction with the coactivator EP300 was subsequently validated in both basal cells and SQCCs, and we demonstrate that EP300 is necessary for SOX2 activity in basal cells, including for induction of the squamous fate. We also report that EP300 copy number gains are common in SQCCs and that growth of lung cancer cell lines with 3q gains, including SQCC cells, is dependent on EP300. Finally, we show that EP300 inhibitors can be combined with other targeted therapeutics to achieve more effective growth suppression. Our work supports the use of BioID to identify interacting protein partners of nondruggable oncoproteins such as SOX2, as an effective strategy to discover biologically relevant, druggable targets. Lung cancer is the leading cause of cancer mortality worldwide (1.Torre L.A. Bray F. Siegel R.L. Ferlay J. Lortet-Tieulent J. Jemal A. Global cancer statistics, 2012.CA. Cancer J. Clin. 2015; 65: 87-108Crossref PubMed Scopus (20110) Google Scholar). Squamous cell carcinoma (SQCC) 1The abbreviations used are: SQCC, squamous cell carcinoma; ADC, adenocarcinoma; AP-MS, affinity purification-mass spectrometry; SAINT, significance analysis of the interactome; FDR, false discovery rate; TCGA, The Cancer Genome Atlas; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PDX, primary patient-derived tumor xenograft; PLA, proximity ligation assay; AML, acute myeloid leukemia; HAT, histone acetyltransferase; CCLE, Cancer Cell Line Encyclopedia; ATCC, American Type Culture Collection; ES, embryonic stem. 1The abbreviations used are: SQCC, squamous cell carcinoma; ADC, adenocarcinoma; AP-MS, affinity purification-mass spectrometry; SAINT, significance analysis of the interactome; FDR, false discovery rate; TCGA, The Cancer Genome Atlas; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PDX, primary patient-derived tumor xenograft; PLA, proximity ligation assay; AML, acute myeloid leukemia; HAT, histone acetyltransferase; CCLE, Cancer Cell Line Encyclopedia; ATCC, American Type Culture Collection; ES, embryonic stem. is the second most common form of lung cancer and generally develops over many years through successive premalignant changes in the bronchial epithelium (2.Ishizumi T. 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Moving beyond the androgen receptor (AR): targeting AR-interacting proteins to treat prostate cancer.Hormones Cancer. 2016; 7: 84-103Crossref PubMed Scopus (0) Google Scholar). Because PI3K cooperates with SOX2 to drive the squamous injury response in stem cells (28.Kim B.R. Van de Laar E. Cabanero M. Tarumi S. Hasenoeder S. Wang D. Virtanen C. Suzuki T. Bandarchi B. Sakashita S. Pham N.A. Lee S. Keshavjee S. Waddell T.K. Tsao M.S. Moghal N. SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis.PLos Biol. 2016; 14: e1002581Crossref PubMed Scopus (18) Google Scholar), PI3K inhibitors could theoretically be used in the treatment of SOX2-driven neoplasias. However, in a phase II SQCC clinical trial, the PI3K inhibitor BKM120 was ineffective at its maximum tolerated dose (41.Vansteenkiste J.F. Canon J.L. Braud F.D. Grossi F. De Pas T. Gray J.E. Su W.C. Felip E. Yoshioka H. Gridelli C. Dy G.K. Thongprasert S. Reck M. Aimone P. Vidam G.A. Roussou P. Wang Y.A. Di Tomaso E. Soria J.C. Safety and efficacy of buparlisib (BKM120) in patients with PI3K pathway-activated non-small cell lung cancer: results from the phase II BASALT-1 study.J. Thoracic Oncol. 2015; 10: 1319-1327Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Whereas PI3K inhibitors might be more effective during preneoplasia, their effectiveness in SQCC might be improved by combining them with drugs that more directly target SOX2 activity. Such drugs could inhibit protein-protein interactions or the activity of chromatin modifying enzymes that are essential for SOX2-dependent effects on transcription. For example, small molecules that inhibit the interaction between TP53 and MDM2, or interactions between BET domain-containing proteins and acetyl-lysine residues, are in clinical trials (42.Andreeff M. Kelly K.R. Yee K. Assouline S. Strair R. Popplewell L. Bowen D. Martinelli G. Drummond M.W. Vyas P. Kirschbaum M. Iyer S.P. Ruvolo V. Gonzalez G.M. Huang X. Chen G. Graves B. Blotner S. Bridge P. Jukofsky L. Middleton S. Reckner M. Rueger R. Zhi J. Nichols G. Kojima K. Results of the phase I trial of RG7112, a small-molecule MDM2 antagonist in leukemia.Clin. Cancer Res. 2016; 22: 868-876Crossref PubMed Scopus (136) Google Scholar) (e.g. GSK525762, https://clinicaltrials.gov). In addition, romidepsin and vorinostat are histone deacetylase inhibitors that are approved for treatment of cutaneous T-cell lymphoma (43.Zinzani P.L. Bonthapally V. Huebner D. Lutes R. Chi A. Pileri S. Panoptic clinical review of the current and future treatment of relapsed/refractory T-cell lymphomas: Cutaneous T-cell lymphomas.Crit. Rev. Oncol. Hematol. 2016; 99: 228-240Crossref PubMed Google Scholar), whereas histone methyltransferase inhibitors are in clinical trials for different cancers (e.g. EPZ-5676, https://clinicaltrials.gov). 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