The HPV E6 oncoprotein targets histone methyltransferases for modulating specific gene transcription

Abstract

Expression of viral proteins causes important epigenetic changes leading to abnormal cell growth. Whether viral proteins directly target histone methyltransferases (HMTs), a key family enzyme for epigenetic regulation, and modulate their enzymatic activities remains elusive. Here we show that the E6 proteins of both low-risk and high-risk human papillomavirus (HPV) interact with three coactivator HMTs, CARM1, PRMT1 and SET7, and downregulate their enzymatic activities in vitro and in HPV-transformed HeLa cells. Furthermore, these three HMTs are required for E6 to attenuate p53 transactivation function. Mechanistically, E6 hampers CARM1- and PRMT1-catalyzed histone methylation at p53-responsive promoters, and suppresses the binding of p53 to chromatinized DNA independently of E6-mediated p53 degradation. p53 pre-methylated at lysine-372 (p53K372 mono-methylation) by SET7 protects p53 from E6-induced degradation. Consistently, E6 downregulates p53K372 mono-methylation and thus reduces p53 protein stability. As a result of the E6-mediated inhibition of HMT activity, expression of p53 downstream genes is suppressed. Together, our results not only reveal a clever approach for the virus to interfere with p53 function, but also demonstrate the modulation of HMT activity as a novel mechanism of epigenetic regulation by a viral oncoprotein.

The role of PRDMs in cancer: one family, two sides

“…PRDM14 was silenced through hypermethylation of its promoter, and ectopic expression of PRDM14 induced apoptosis [72]. This could be due to the diverse genetic make-up of the different cancers studied, or could be dependent on expression of HPV oncogenic proteins, which could in turn interact with, and either sequester or inactivate, transcriptional cofactors necessary for PRDM14 activity [73]. Mechanistically, PRDM14 has been shown to associate with EZH2/H3K27me3 repressive activity, which in ES cells is essential to maintain the naïve state of pluripotency.…”

Methyltransferase PRMT1 Is a Binding Partner of HBx and a Negative Regulator of Hepatitis B Virus Transcription

“…Interestingly, by inhibiting PRMT1, HCV modulates the expression of cellular genes involved in hepatocarcinogenesis and inhibits DNA repair damage, suggesting a role of PRMT1 inhibition in HCV-mediated HCC (73). Similarly, the E6 oncoproteins of low-risk and highrisk human papillomavirus interact with histone methyltransferases CARM1, PRMT1, and SET7, inhibiting their activities, which leads to the suppression of p53 activity (74). Together with our current study, these results emphasize the important role of arginine methyltransferases in virus replication and associated pathogenesis.…”

Papillomavirus E6 oncoproteins

“…HrE6 also modulates the function of other chromatin modifiers including CARM1, PRMT1 and SET7 to negatively regulate their activity, inhibit p53 activation of transcription and enhance the degradation of p53 by hrE6 (Hsu et al, 2012). …”