CREB1 activation promotes human papillomavirus oncogene expression and cervical cancer cell transformation

Abstract

Human papillomaviruses (HPVs) infect the oral and anogenital mucosa and can cause cancer. The high‐risk (HR)‐HPV oncoproteins, E6 and E7, hijack cellular factors to promote cell proliferation, delay differentiation and induce genomic instability, thus predisposing infected cells to malignant transformation. cAMP response element (CRE)‐binding protein 1 (CREB1) is a master transcription factor that can function as a proto‐oncogene, the abnormal activity of which is associated with multiple cancers. However, little is known about the interplay between HPV and CREB1 activity in cervical cancer or the productive HPV lifecycle. We show that CREB is activated in productively infected primary keratinocytes and that CREB1 expression and phosphorylation is associated with the progression of HPV+ cervical disease. The depletion of CREB1 or inhibition of CREB1 activity results in decreased cell proliferation and reduced expression of markers of epithelial to mesenchymal transition, coupled with reduced migration in HPV+ cervical cancer cell lines. CREB1 expression is negatively regulated by the tumor suppressor microRNA, miR‐203a, and CREB1 phosphorylation is controlled through the MAPK/MSK pathway. Crucially, CREB1 directly binds the viral promoter to upregulate transcription of the E6/E7 oncogenes, establishing a positive feedback loop between the HPV oncoproteins and CREB1. Our findings demonstrate the oncogenic function of CREB1 in HPV+ cervical cancer and its relationship with the HPV oncogenes.

E7-mediated repression of miR-203 promotes LASP1-dependent proliferation in HPV-positive cervical cancer

“…As we previously demonstrated, miR-203 significantly reduced cell growth and colony formation in HPV+ cervical cancer cells (Fig. 5C-E; (40)).…”

“…miRNAs regulate many fundamental cellular functions, such as transcription, post-transcriptional modifications, and signal transduction (54). Data from our lab and others has shown that miR-203a, a well-studied tumour suppressor, is downregulated by HPV E6 and E7 (40,(46)(47)(48). We have previously shown that the targeting of CREB1 is partially responsible for the proliferation defects observed upon miR-203 re-introduction in HPV+ cervical cancer cells (40).…”

“…Furthermore, LASP1 has previously been shown to be regulated by several miRNAs in diverse cancers (25,(41)(42)(43)(44)(45). Of these, we and others have previously shown that miR-203 is downregulated in cervical cancer (40,(46)(47)(48). To understand if miR-203 regulates LASP1 in cervical cancer, we first analysed the panel of cervical cytology samples and observed a significant inverse correlation between miR-203 levels and LASP1 mRNA expression (Fig.…”

“…Previous studies have shown that HPV can manipulate miRNA networks to promote cellular transformation (16,(38)(39)(40). miRNAs regulate many fundamental cellular functions, such as transcription, post-transcriptional modifications, and signal transduction (54).…”

“…LASP1 expression is regulated by miR-203 in an E7-dependent manner. HPV E6 and E7 manipulate microRNA (miRNA) networks in order to control host gene expression (16,(38)(39)(40). Furthermore, LASP1 has previously been shown to be regulated by several miRNAs in diverse cancers (25,(41)(42)(43)(44)(45).…”