Histone Demethylase KDM5B Collaborates with TFAP2C and Myc To Repress the Cell Cycle Inhibitor p21 ^cip ( CDKN1A )

Abstract

The TFAP2C transcription factor has been shown to downregulate transcription of the universal cell cycle inhibitor p21 cip (CDKN1A). In examining the mechanism of TFAP2C-mediated repression, we have identified a ternary complex at the proximal promoter containing TFAP2C, the oncoprotein Myc, and the trimethylated lysine 4 of histone H3 (H3K4me3) demethylase, KDM5B. We demonstrated that while TFAP2C and Myc can downregulate the CDKN1A promoter independently, KDM5B acts as a corepressor dependent on the other two proteins. All three factors collaborate for optimal CDKN1A repression, which requires the AP-2 binding site at ؊111/؊103 and KDM5B demethylase activity. Silencing of TFAP2C-KDM5B-Myc led to increased H3K4me3 at the endogenous promoter and full induction of CDKN1A expression. Coimmunoprecipitation assays showed that TFAP2C and Myc associate with distinct domains of KDM5B and the TFAP2C C-terminal 270 amino acids (aa) are required for Myc and KDM5B interaction. Overexpression of all three proteins resulted in forced S-phase entry and attenuation of checkpoint activation, even in the presence of chemotherapy drugs. Since each protein has been linked to poor prognosis in breast cancer, our findings suggest that the TFAP2C-Myc-KDM5B complex promotes cell cycle progression via direct CDKN1A repression, thereby contributing to tumorigenesis and therapy failure.

The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells

“…1D). As positive controls ChIPs of CDKN1a, coding for the cell cycle inhibitor p21 22 , and dihydrofolate reductase (DHFR) 23 that are c-Myc target genes were included. Of note, we detected even higher levels of binding of c-Myc and Max to the B7-H6 gene as compared to the positive controls.…”

Original Research: miR-194 inhibits proliferation and invasion and promotes apoptosis by targeting KDM5B in esophageal squamous cell carcinoma cells

“…25 Wong et al reported that KDM5B collaborates with TFAP2C and Myc to suppress the cell cycle inhibitor p21 cip . 26 Enkhbaatar et al reported that ectopic expression of KDM5B promotes epithelial-mesenchymal transition (EMT) of cancer cells. 27 Li et al reported that KDM5B is highly expressed in prostate cancer cells and promotes proliferation and inhibits apoptosis of prostate cancer cells.…”

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

“…KDM5B-mediated histone H3K4 demethylation contributes to the silencing of retinoblastoma target genes in senescent cells, presumably by compacting chromatin and silencing certain genes [13,14]. Previous studies have found that KDM5B depletion stimulated p16 and p21 transcription and suppressed tumor cell growth in vitro and in vivo [15,16], suggesting that it plays a role in cell growth regulation in human cancer.…”