THE STUDY OF A NOVEL MIXED LINEAGE LEUKEMIA 5 ISOFORM AND ITS ASSOCIATION WITH HUMAN PAPILLOMAVIRUS 16/18 - RELATED HUMAN CERVICAL CANCERS

Abstract

Human papillomavirus (HPV) is the primary cause of human cervical cancer. The viral proteins E6 and E7 are essential to transform non-cancerous epithelial cells into cancerous carcinomas by targeting key tumour suppressors p53 and retinoblastoma proteins. In this study, we defined a novel Mixed Lineage Leukemia 5 isoform (MLL5ß) as a specific and critical regulator of E6 and E7 transcription in cervical carcinoma cells. MLL5ß is present exclusively in HPV16/18-positive cells including human primary cervical carcinoma specimens. Interaction of MLL5ß with the AP-1 binding site at the distal region of HPV18 long control region led to activation of E6/E7 transcription. Conversely, RNAi-mediated knockdown of MLL5ß downregulated both E6 and E7 expression. MLL5ß downregulation was sufficient to restore p53 protein levels and reduce Rb phosphorylation, thereby re-activating apoptosis and cell cycle checkpoints. Our work highlights the potential of MLL5ß as a biomarker and new therapeutic target in primary HPV-induced cervical cancers.