A Novel MLL5 Isoform That Is Essential to Activate E6 and E7 Transcription in HPV16/18-Associated Cervical Cancers

Human papillomavirus (HPV) is the primary cause of human cervical cancer. The viral proteins E6 and E7 are essential to transform noncancerous epithelial cells into cancerous carcinomas by targeting key tumor suppressors p53 and retinoblastoma (Rb) proteins, respectively, but the cellular factors involved in E6 and E7 transcription themselves are incompletely understood. In this study, we defined a novel isoform of the mixed lineage leukemia 5 gene (MLL5 beta) as a specific and critical regulator of E6 and E7 transcription in cervical carcinoma cells. MLL5 beta b is present in HPV16/18-positive cells including human primary cervical carcinoma specimens. Interaction of MLL5 beta with the AP-1-binding site at the distal region of the HPV18 long control region led to activation of E6/E7 transcription. Conversely, RNA interference-mediated knockdown of MLL5 beta down-regulated both E6 and E7 expression. MLL5 beta downregulation was sufficient to restore p53 protein levels and reduce Rb phosphorylation, thereby reactivating apoptosis and cell-cycle checkpoints. By defining this novel MLL5b isoform and its specific critical role in activating E6/E7 gene transcription in HPV16/18-induced cervical cancers, our work highlights the potential of MLL5 beta as a biomarker and new therapeutic target in primary HPV-induced cervical cancers. Cancer Res; 71(21); 6696-707. (C)2011 AACR.