E6AP goes viral: the role of E6AP in viral- and non-viral-related cancers

Abstract

Since its discovery, the E3 ubiquitin ligase E6-associated protein (E6AP) has been studied extensively in two pathological contexts: infection by the human papillomavirus (HPV), and the neurodevelopmental disorder, Angelman syndrome. Vital biological links between E6AP and other viruses, namely hepatitis C virus and encephalomyocarditis virus, have been recently uncovered. Critically, oncogenic E6AP activities have been demonstrated to contribute to cancers of both viral and non-viral origins. HPV-associated cancers serve as the primary example of E6AP involvement in cancers driven by viruses. Studies over the past few years have exposed a role for E6AP in non-viral-related cancers. This has been demonstrated in B-cell lymphoma and prostate cancers, where oncogenic E6AP functions drive these cancers by acting on key tumour suppressors. In this review we discuss the role of E6AP in viral infection, viral propagation and viral-related cancer. We discuss processes affected by oncogenic E6AP, which promote cancers of viral and non-viral aetiology. Overall, recent findings support the role of oncogenic E6AP in disrupting key cellular processes, including tumour suppression and the immune response. E6AP is consequently emerging as an attractive therapeutic target for a number of specific cancers.

HPV 16 E6 Promotes Growth and Metastasis of Esophageal Squamous Cell Carcinoma cells in vitro

“…In this study, we found that the mRNA level of P53 and miR-34a had signi cantly decreased in HPV-infected Ec109 and Ec9706 cell lines, which demonstrated that the expression of p53 and miR-34a may be also closely related in HPV-infected ESCC cells. Studies have suggested that the combination of p53 and E6 is E6AP dependent [51][52][53], and in human papillomavirus-induced cancer, E6 recruits E6AP and subsequently induces proteasomedependent p53 degradation [54,55]. In our experiment, the mRNA level of E6AP had signi cantly decreased with the decrease of P53 in HPV-infected ESCC cells, which indicates that HPV infection may also mediate the degradation of p53 through E6/E6AP in ESCC.…”

Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors

“…EMCV is not known to cause cancer but it has been shown that it can induce autoimmune reactions against T cells, fostering the development of type 1 diabetes [ 178 ]. It can also interfere with the cellular E3 ubiquitin ligase E6‐associated protein (E6AP) [ 179 ], which regulates cell proliferation via the PI3K‐AKT signalling pathway [ 180 ]. In the present study, the detection of EMCV sequences in liver metastasis again raises the question whether this virus might be contributing to aspects of inflammation, carcinogenesis or microenvironmental interactions in CRC.…”

The HECT E3 Ligase E6AP/UBE3A as a Therapeutic Target in Cancer and Neurological Disorders

“…The discovery of E6AP lends itself to the seminal finding that the human papillomavirus (HPV) oncoprotein E6 mediates degradation of the tumor suppressor protein p53 by activating this E3 [ 19 ], which is a classic example of the downregulation of tumor suppressors by viral oncoproteins. E6AP has been studied for its involvement in not only viral oncogenesis but also non-viral oncogenesis [ 20 , 21 , 22 , 23 ], as recently reviewed by Bandilovska et al [ 24 ]. Here, we focus on the roles of diverse targets of E6AP in various cancers, as summarized in Table 1 .…”