CIP2A facilitates the G1/S cell cycle transition via B-Myb in human papillomavirus 16 oncoprotein E6-expressing cells.

Yonghao Tian,Weiming Zhao,Lijun Qiao,Wenhao Zhang,Hanxiang Chen,Jason J Chen,Weifang Zhang,Jingyi Zheng

doi:10.1111/jcmm.13693

Abstract

Infection with high‐risk human papillomaviruses (HR‐HPVs, including HPV‐16, HPV‐18, HPV‐31) plays a central aetiologic role in the development of cervical carcinoma. The transforming properties of HR‐HPVs mainly reside in viral oncoproteins E6 and E7. E6 protein degrades the tumour suppressor p53 and abrogates cell cycle checkpoints. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that is involved in the carcinogenesis of many human malignancies. Our previous data showed that CIP2A was overexpressed in cervical cancer. However, the regulation of CIP2A by HPV‐16E6 remains to be elucidated. In this study, we demonstrated that HPV‐16E6 significantly up‐regulated CIP2A mRNA and protein expression in a p53‐degradation‐dependent manner. Knockdown of CIP2A by siRNA inhibited viability and DNA synthesis and caused G1 cell cycle arrest of 16E6‐expressing cells. Knockdown of CIP2A resulted in a significant reduction in the expression of cyclin‐dependent kinase 1 (Cdk1) and Cdk2. Although CIP2A has been reported to stabilize c‐Myc by inhibiting PP2A‐mediated dephosphorylation of c‐Myc, we have presented evidence that the regulation of Cdk1 and Cdk2 by CIP2A is dependent on transcription factor B‐Myb rather than c‐Myc. Taken together, our study reveals the role of CIP2A in abrogating the G1 checkpoint in HPV‐16E6‐expressing cells and helps in understanding the molecular basis of HPV‐induced oncogenesis.

Highlights

Human papillomavirus (HPV) is a small DNA virus that replicates in the stratified layers of skin and mucosa and is one of the most common sexually transmitted infections
By retrovirus-mediated overexpressing of HPV-16E6 and E6 mutantF2V, on the one hand, we showed that 16E6 significantly increased Cancerous inhibitor of protein phosphatase 2A (CIP2A) mRNA and protein expression in a p53-degradation–dependent manner
Knockdown of CIP2A caused a reduction in the expression of p53 in HPV-16E6-expressing cells

Summary

| INTRODUCTION

Human papillomavirus (HPV) is a small DNA virus that replicates in the stratified layers of skin and mucosa and is one of the most common sexually transmitted infections. The high-risk HPV type infections are associated with cervical carcinoma, which is one of the leading causes of cancer death in women worldwide.[1] In addition, HPV infections are linked to more than 50% of other anogenital cancers and cancers of the oesophagus.[2] tobacco and alcohol are responsible for most head and neck squamous cell carcinomas (HNSCCs), there is evidence for a causal association between HPV infections and HNSCCs. Despite a steady decrease in the number of overall HNSCCs cases in the past decades, the incidence of oropharyngeal cancer has increased significantly.[3] Notably, in the meantime, the HPV DNA detection rate has increased from 16.3% to 71.7% in oropharyngeal cancer.[4]. CIP2A is related to a poor patient prognosis and may be applied as a prognosis biomarker in evaluating the risk of tumour metastasis It is overexpressed in 70% of most solid malignancies samples, while it is rarely expressed in normal tissues, which makes CIP2A a possible therapeutic target (for a review see Ref.[12]). We showed that HPV-16E6 protein up-regulated CIP2A by degrading p53 in 16E6-expressing cells and that CIP2A facilitated the G1/S transition by modulating Cdk[1] and Cdk[2] proteins in a B-Myb–dependent manner

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION