E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C

Abstract

The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes and Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like and This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. .

KDM5 histone demethylases repress immune response via suppression of STING

“…In line with the oncogenic roles of KDM5A and KDM5B, suppression of KDM5A or KDM5B delays tumor formation, metastasis, and drug resistance in breast, lung, melanoma, and gastric cancers [ 17 , 21 – 29 ]. Although inhibition of KDM5C could have adverse effects on neuronal circuits [ 62 ] or promote tumor formation in clear cell renal carcinoma [ 63 ] and cervical cancer [ 64 ], KDM5C was also shown to have oncogenic roles in prostate cancer [ 65 ].…”

KDM5C Represses FASN-Mediated Lipid Metabolism to Exert Tumor Suppressor Activity in Intrahepatic Cholangiocarcinoma

“…KDM5C has also been observed to be overexpressed and promote tumor growth in prostate cancer ( 14 ). In contrast, KDM5C plays a tumor-suppressing role in cervical cancer, breast cancer and renal carcinoma ( 15 – 17 ). Nevertheless, the exact effect of KDM5C on ICC is unclear.…”

Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway

“…They are potent mediators of communication between cancer cells and their surrounding microenvironment, which contains various types of host cells, including HUVECs [16][17][18][19][20][21][22][23]35]. Given that E6 oncoproteins are the critical drivers of HPV 16/18-associated CC development [36,37], we hypothesized that HPV 16/18 E6 in uences the TME via EVs. As expected, we observed that EVs derived from the four HPV 16/18 E6-KD cell lines and corresponding control cells were effectively internalized by HUVECs.…”