Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer

Abstract

Epigenetic modifications are known to play critical roles in the expression of genes related to differentiation and dedifferentiation. Histone lysine demethylase KDM5B (PLU-1) catalyzes the demethylation of histone H3 on Lys 4 (H3K4), which results in the repression of gene expression. KDM5B is involved in regulation of luminal and basal cell specific gene expression in breast cancers. However, the mechanisms by which KDM5B is regulated in breast cancer, in particular in response to post-translational signals is not well-defined. Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes. Moreover, KDM5B inhibited the expression of pluripotency genes, SOX2 and NANOG, and decreased the stem cell population in triple-negative breast cancer cell lines (TNBC). We previously reported that the tumor suppressor HEXIM1 is a mediator of KDM5B recruitment to its target genes, and HEXIM1 is required for the inhibition of nuclear hormone receptor activity by KDM5B. Similarly, HEXIM1 is required for regulation of pluripotency genes by KDM5B.

Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer

“…Not surprisingly, KDM5B is overexpressed, and has been reported to play an oncogenic function, in a variety of cancers including breast cancer [4,22], melanoma [26], PCa [27], lung cancer [28], hepatocellular carcinoma [29], gastric cancer [30], neuroblastoma [31] and leukemia [32]. On the other hand, potential tumor-suppressive functions of KDM5B have also been documented in some cases of melanoma and subtypes of breast cancer [33,34]. Mechanistically, KDM5B has been reported to interact with transcription factors such as estrogen receptor α (ERα), androgen receptor (AR), progesterone receptor, PAX9, FOXG1, etc, and such interactions direct its localization to a diverse repertoire of genes in different cell types that further leads to distinct gene expression and contributes to CTH and intratumor heterogeneity [6].…”

Physical association of functionally antagonistic enzymes: KDM5A interacts with MLLs to regulate gene expression in a promoter specific manner facilitating EMT and pluripotency

“…As the catalytically inactive or kinase-dead mutants of FAK generally localize to nucleus and nuclear FAK regulate gene expression by interacting with epigenetic modifiers like HDAC1, MBD2 and Sin3a (43), all of which interact with KDM5A ( 9) and increased KDM5A occupancy didn't downregulate E-cadherin expression, it was concluded that FAK inhibition somehow rendered KDM5A inactive. We speculate that a phosphorylation dependent activation mechanism might persist between FAK and KDM5A as KDM5 family members localization and enzymatic activity was earlier reported to be regulated by phosphorylation through AKT/CDKs (44,45). The differential expression profile of KDM5A-MLL2 in HeLa-HaCaT cell lines (this study) compared to HCT15-A498 (our unpublished data) could be attributed to FAK localization in these cell lines as in colon cancer, phosphorylated FAK localized to nucleus compared to ovarian cancer which exhibited both cytosolic and nuclear distribution (43).…”

Post-translational modification analysis of Saccharomyces cerevisiae histone methylation enzymes reveals phosphorylation sites of regulatory potential

“…Our model also highlights the diversity of signaling kinases and pathways that are predicted to regulate the histone methylation network. These pathways, such as the cyclin-dependent, mitogen-activated, and DNA damage response signaling cascades, are not unexpected as they are known to be associated with changes in mammalian chromatin (25,27,(67)(68)(69).…”