ACK1 Tyrosine Kinase Interacts with Histone Demethylase KDM3A to Regulate the Mammary Tumor Oncogene HOXA1

Abstract

Background:The molecular mechanism by which tyrosine kinases promote estrogen-independent ER-responsive gene expression is poorly understood. Results: ACK1 drives the expression of oncogene HOXA1 by stimulating KDM3A histone demethylase activity by tyrosine phosphorylation. Conclusion: Targeting ACK1 signaling by AIM-100 mitigates HOXA1 expression and inhibits breast cancer cell growth. Significance: ACK1⅐KDM3A⅐HOXA1 signaling represents a novel target in overcoming tamoxifen resistance.

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

“…AR has been shown to regulate MYC transcription program in an androgen-independent manner (Gao et al, 2013), which explains the significant loss of MYC-target gene expression upon ( R )-9bMS treatment. Intriguingly, these data also suggest a role for ACK1 in driving ER-mediated transcription which is consistent with our earlier observation wherein ACK1 interacts with ER and its co-activator histone demethylase KDM3A (Mahajan et al, 2014). Combined, these results illustrate targeting of major survival pathways by ACK1 inhibitor underlie its effectiveness in restraining the growth of PC cells.…”

HOX genes: Major actors in resistance to selective endocrine response modifiers

“…The complex of activated ACK1, ER and KDM3A binds to the HOXA1 promoter regions directly and regulates HOXA1 transcriptional activity. These results suggest that the ACK1-KDM3A-HOXA1 signaling axis might be a new target in acquired tamoxifen-resistant breast cancer [55]. Another HOXA protein, HOXA7, influences ER expression in MCF-7 cells.…”

“…In endometrial cells, HOXA10 expression is regulated by estrogen and tamoxifen [54]. HOXA1 is also an estrogen-responsive gene [55]. The authors show that ACK1, a ubiquitously expressed non-receptor tyrosine kinase, interacts with ER and the ER co-activator, KDM3A, a H3K9 demethylase, by phosphorylation in presence of tamoxifen.…”

The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer

“…Jumonji C domain‐containing histone demethylases (JDHD) remove methyl groups from histone lysines; during this reaction, they decarboxylate α‐ketoglutarate to succinate . JDHD demethylation of lysines was shown to increase transactivation of the androgen receptor and oestrogen receptor (ER), increasing expression of the homeobox transcription factor HOXA1 . Similarly, demethylation has been shown to be critical for the activities of the oestrogen receptor (ER) through regulation of GATA‐3 binding at the promoter of the ER gene .…”