Oncotarget

Research Papers:

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

Khalil Ahmad _, Bastian Scholz, Ricardo Capelo, Ilona Schweighöfer, Astrid Stefanie Kahnt, Rolf Marschalek and Dieter Steinhilber

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Oncotarget. 2015; 6:25784-25800. https://doi.org/10.18632/oncotarget.4703

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Abstract

Khalil Ahmad1, Bastian Scholz2, Ricardo Capelo1, Ilona Schweighöfer1, Astrid Stefanie Kahnt1, Rolf Marschalek2,*, Dieter Steinhilber1,*

1Institute of Pharmaceutical Chemistry / ZAFES Goethe University Frankfurt

2Institute of Pharmaceutical Biology / ZAFES, Goethe University Frankfurt, Germany

*These authors contributed equally to this work

Correspondence to:

Dieter Steinhilber, e-mail: [email protected]

Rolf Marschalek, e-mail: [email protected]

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 D3) 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.


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