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AF4 and AF4-MLL mediate transcriptional elongation of 5-lipoxygenase mRNA by 1, 25-dihydroxyvitamin D3

2015; Impact Journals LLC; Volume: 6; Issue: 28 Linguagem: Inglês

10.18632/oncotarget.4703

1949-2553

Khalil Ali Ahmad, Bastian Scholz, Ricardo Capelo, Ilona Schweighöfer, Astrid S. Kahnt, Rolf Marschalek, Dieter Steinhilber,

Protein Degradation and Inhibitors

// Khalil Ahmad 1 , Bastian Scholz 2 , Ricardo Capelo 1 , Ilona Schweighöfer 1 , Astrid Stefanie Kahnt 1 , Rolf Marschalek 2, * , Dieter Steinhilber 1, * 1 Institute of Pharmaceutical Chemistry / ZAFES Goethe University Frankfurt 2 Institute of Pharmaceutical Biology / ZAFES, Goethe University Frankfurt, Germany * These authors contributed equally to this work Correspondence to: Dieter Steinhilber, e-mail: steinhilber@em.uni-frankfurt.de Rolf Marschalek, e-mail: rolf.marschalek@em.uni-frankfurt.de Keywords: 5-lipoxygenase, MLL, AF4, calcitriol, HDAC Received: March 09, 2015 Accepted: July 10, 2015 Published: July 27, 2015 ABSTRACT The human 5-lipoxygenase (5-LO), encoded by the ALOX5 gene, is the key enzyme in the formation of pro-inflammatory leukotrienes. ALOX5 gene transcription is strongly stimulated by calcitriol (1α, 25-dihydroxyvitamin D 3 ) and TGFβ (transforming growth factor-β). Here, we investigated the influence of MLL (activator of transcript initiation), AF4 (activator of transcriptional elongation) as well as of the leukemogenic fusion proteins MLL-AF4 (ectopic activator of transcript initiation) and AF4-MLL (ectopic activator of transcriptional elongation) on calcitriol/TGFβ-dependent 5-LO transcript elongation. We present evidence that the AF4 complex directly interacts with the vitamin D receptor (VDR) and promotes calcitriol-dependent ALOX5 transcript elongation. Activation of transcript elongation was strongly enhanced by the AF4-MLL fusion protein but was sensitive to Flavopiridol. By contrast, MLL-AF4 displayed no effect on transcriptional elongation. Furthermore, HDAC class I inhibitors inhibited the ectopic effects caused by AF4-MLL on transcriptional elongation, suggesting that HDAC class I inhibitors are potential therapeutics for the treatment of t(4;11)(q21;q23) leukemia.