Promoter occupancy of MLL1 histone methyltransferase seems to specify the proliferative and apoptotic functions of E2F1 in a tumour microenvironment

Abstract

The E2F family of transcription factors are considered versatile modulators, poised at biological crossroads to execute diverse cellular functions. Despite extensive studies on E2F, the molecular mechanisms that control specific biological functions of the E2F1 transcription factor are still not fully understood. Here we have addressed the molecular underpinnings of paradoxical functions of E2F1 in a tumour microenvironment using the 'X15-myc' oncomouse model of hepatocellular carcinoma. We observed that the HBx oncoprotein of hepatitis B virus regulates E2F1 functions by interfering with its binding to Skp2 E3 ubiquitin ligase. The HBx-Skp2 interaction led to the accumulation of transcriptionally active E2F1 and histone methyltransferase mixed lineage leukemia 1 (MLL1) protein. During early stages of hepatocarcinogenesis, the increased E2F1 activity promoted cellular proliferation by stimulating the genes involved in cell cycle control and replication. However, during the late stages, E2F1 triggered replication-stress-induced DNA damage and sensitized cells to apoptotic death in a p53-independent manner. Interestingly, the different promoter occupancy of MLL1 during the early and late stages of tumour development seemed to specify the proliferative and apoptotic functions of E2F1, through its dynamic interaction with the co-activator CBP or co-repressor Brg1. Thus, the temporally regulated promoter occupancy of histone methyltransferase could be a regulatory mechanism associated with the diverse cellular functions of the E2F family of transcription factors.