HPV16 infection regulates RASSF1A transcription mediated by p53

Abstract

Human papillomavirus (HPV) 16 infection and RASSF1A expression play important roles in tumor development and progression. However, the precise mechanisms underlying their concerted function in the development of reproductive system tumors still remain to be elucidated. In the present study, we showed that HPV16-E6 selectively upregulates RASSF1A expression via degradation of p53, which interacts with the RASSF1A promoter and regulates apoptosis. Overexpression of p53 triggered a decrease in endogenous RASSF1A in SiHa cells, accompanied by apoptosis. Similarly, knockdown of endogenous HPV16-E6 in SiHa cells with RNA interference (RNAi) led to downregulation of RASSF1A mediated by p53 and the subsequent induction of apoptosis. These findings collectively suggest that HPV16 infection regulates p53-mediated RASSF1A expression and suppresses apoptosis. Moreover, RASSF1A may form an element of the negative autoregulatory feedback loops that act on the HPV16 response and are involved in p53-dependent apoptosis. Our results provide novel insights into the cellular mechanism of tumor development, and present a starting point for the development of novel strategies in cancer treatment and effective diagnosis.

The tumor suppressor RASSF1A induces the YAP1 target gene ANKRD1 that is epigenetically inactivated in human cancers and inhibits tumor growth

“…The oncogenic function of YAP1 is mediated through the TEAD complex and the activation of proliferative genes like CTGF and cyclin D1 [ 8 , 17 ]. It has been reported that p53 directly regulates the expression of RASSF1A [ 26 , 28 ] and that the loss of RASSF1A promotes the formation of an oncogenic YAP1-TEAD complex [ 46 ]. In this context, it is important to note that TREx293, which are derived from HEK293 cells exhibit a RASSF1A promoter hypermethylation ( Supplementary Figure 5 ).…”

Significant decrease of a master regulator of genes (REST/NRSF) in high-grade squamous intraepithelial lesion and cervical cancer

“…We found no association between REST and RASSF1A expression with HPV genotypes or with the integrated viral state. Previously, a link between increase of p53 and decrease of RASSF1A expression [ 29 ], and HPV-16 E6/E7 expression with aberrant methylation and RASSF1A expression, has been reported [ 44 ]. In this study, we did not find a relation between REST and RASSF1A protein expression levels.…”

“…The RE-1 sequences in RASSF1A were analyzed using Pairwise Sequence Alignment in the Matcher (EMBOSS) server in the EMBL-EBI ( https://www.ebi.ac.uk/Tools/psa/emboss_matcher/ ) [ 28 ]. p53 union site was previously reported [ 29 ]. CpG island content was analyzed at Data Base of CpG island and analytical tool (DBCAT: http://dbcat.cgm.ntu.edu.tw/ ).…”

RASSF1A Tumour Suppressor: Target the Network for Effective Cancer Therapy

“…The mechanisms that regulate HV-dependent DNA methylation are not completely understood, but they are likely to be mediated by inflammatory signals and direct regulation of DNMTs by viral proteins, such as HBx [29]. Additionally, important evidence links RASSF1A hypermethylation to human papilloma virus (HPV) infection-dependent cervical carcinoma and it might prevent the activation of p53 antioncogenic signals [30][31][32][33]. Importantly, the silencing of RASSF1A by hypermethylation has been shown to occur at the same time as promoter hypermethylation of the TP73 gene, which is an effector of RASSF1A [34,35].…”