The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis

Abstract

Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)‐target genes, and meanwhile suppresses type I interferons (IFNs) and IFN‐stimulated genes (ISGs) to promote ERα‐positive breast cancer cell growth and tumorigenesis. KDM5C‐interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P‐TEFb complex to activate ERα‐target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.

The cholesterol esterification inhibitor avasimibe suppresses tumour proliferation and metastasis via the E2F-1 signalling pathway in prostate cancer

“…The cells were incubated with 20 µl of MTT (5 mg/ml/well) for 4 h at 37 °C. After discarding the supernatant, the MTT formazan crystals were dissolved in 200 µl/well DMSO, and a microplate reader was applied to measure the OD values at 490 nm [ 19 , 20 ].…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…Similar transcriptional activation functions of KDM5 have been described in mammalian cells. KDM5 physically binds to nuclear receptors, including the estrogen receptor (ER), and enhances their transcriptional activity (Table 1) [36,[48][49][50]. KDM5A also interacts with CLOCK-BMAL1 and enhances CLOCK-BMAL1-mediated transcription by inhibiting HDAC1 function and increasing H3K9 acetylation at the Per2 promoter (Figure 2D) [52].…”

“…KDM5C facilitates castration-resistant prostate cancer cell growth by downregulating PTEN [141]. It promotes breast cancer tumorigenesis by activating ERα-target genes or repressing BRMS1 expression and protects breast cancer cells from immune surveillance by repressing type I interferons and interferon-stimulated genes [36,142]. KDM5C also plays oncogenic roles in gastric cancer, colon cancer, hepatocellular carcinoma, and lung cancer by suppressing p53, FBXW7, BMP7, and miR-133a, respectively [143][144][145][146].…”

Disrupting Mechanisms that Regulate Genomic Repeat Elements to Combat Cancer and Drug Resistance

“…A recent study suggests that KDM5B may contribute to SETDB1 recruitment, thereby leading to TE repression in the context of mouse melanoma ( Zhang et al, 2021 ). KDM5 has also been proposed to inhibit phosphorylation and activation of TBK1 in a demethylase-dependent manner, resulting in blunted IFN signaling in breast cancer cells ( Shen et al, 2021 ). In addition, there have been several IO-oriented CRISPR screens in mice that implicate KDM5 as having a tumor-intrinsic role in repressing IO responses ( Manguso et al, 2017 ; Li et al, 2020 ).…”