Cyclooxygenase-2 Transcription Is Regulated by Human Papillomavirus 16 E6 and E7 Oncoproteins: Evidence of a Corepressor/Coactivator Exchange

Kotha Subbaramaiah,Andrew J Dannenberg

doi:10.1158/0008-5472.can-06-4273

Abstract

Cyclooxygenase (COX-2) is overexpressed in human papillomavirus (HPV)-induced diseases, including cervical cancer. Although HPV E6 and E7 oncoproteins have been causally linked to cervical carcinogenesis, their effects on COX-2 gene expression are unknown. Increased levels of COX-2 mRNA, protein, and prostaglandin E(2) synthesis were detected in HPV16 E6- and E7-expressing cervical cancer cells (CaSki and SiHa) compared with an uninfected cervical cancer cell line (C33A). HPV16 E6 and E7 oncoproteins induced COX-2 transcription by activating the epidermal growth factor receptor (EGFR)-->Ras-->mitogen-activated protein kinase pathway. Interestingly, HPV16 oncoproteins stimulated EGFR signaling, in part, by inducing the release of amphiregulin, an EGFR ligand. The inductive effects of HPV16 E6 and E7 were mediated by enhanced binding of activator protein-1 to the cyclic AMP (cAMP)-responsive element (-59/-53) of the COX-2 promoter. The potential contribution of coactivators and corepressors to HPV16 E6- and E7-mediated induction of COX-2 was also investigated. Chromatin immunoprecipitation assays indicated that E6 and E7 oncoproteins induced the recruitment of phosphorylated c-Jun, c-Fos, UbcH5, and cAMP-responsive element binding protein-binding protein/p300 to the COX-2 promoter. In contrast, E6 and E7 inhibited the binding of the histone deacetylase 3-nuclear receptor corepressor (NCoR) complex to the COX-2 promoter. Moreover, overexpression of NCoR blocked E6- and E7-mediated stimulation of the COX-2 promoter. Taken together, these results indicate that HPV16 E6 and E7 oncoproteins stimulated COX-2 transcription by inducing a corepressor/coactivator exchange. To our knowledge, this study also provides the first evidence that NCoR can function as a repressor of COX-2 gene expression.

Highlights

Cervical cancer is the second most common cause of death from cancer among women worldwide and remains a major cause of mortality among women of reproductive age in developing countries [1]
We show that HPV16 E6 and E7 oncoproteins induced COX-2 gene expression
The induction of COX-2 by HPV16 oncoproteins was mediated by activation of the epidermal growth factor receptor (EGFR)!Ras!mitogen-activated protein kinase (MAPK)!activator protein-1 (AP-1) pathway

Summary

Introduction

Cervical cancer is the second most common cause of death from cancer among women worldwide and remains a major cause of mortality among women of reproductive age in developing countries [1]. Doi:10.1158/0008-5472.CAN-06-4273 development of cervical cancer [3]. In addition to modulating tumor suppressors, HPV E6 and E7 oncoproteins have other effects that contribute to carcinogenesis [8, 9]. Prophylactic vaccines have been developed to prevent cervical cancer caused by HPV types 16 and 18 [10]. These vaccines are unlikely to be of significant benefit to the large number of individuals with established lesions who are already infected with oncogenic HPV. A detailed understanding of the mechanisms that are modulated by HPV E6 and E7 oncoproteins could strengthen the rationale for the use of targeted therapies to prevent or treat cervical cancer in infected individuals

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