Restoring the DREAM Complex Inhibits the Proliferation of High-Risk HPV Positive Human Cells.

Abstract

Simple SummaryHuman papillomaviruses are responsible for around 5% of all cancers, and to date there are no anti-viral therapeutics available for treating these cancers. In this report we demonstrate that in HPV positive cells the transcriptional repressor DREAM complex is disrupted by E7 proteins, with a resulting increase in expression of DREAM target genes. Expression of a mutant DREAM component, LIN52 S20C, competes with E7 and partially rescues DREAM complex formation. This restoration attenuates the growth of HPV positive cells, including HPV positive cervical cancer cell lines. We propose that restoration of the DREAM complex in HPV positive cancers is a novel therapeutic approach that could be adapted to aid in the treatment of these cancers.High-risk (HR) human papillomaviruses are known causative agents in 5% of human cancers including cervical, ano-genital and head and neck carcinomas. In part, HR-HPV causes cancer by targeting host-cell tumor suppressors including retinoblastoma protein (pRb) and RB-like proteins p107 and p130. HR-HPV E7 uses a LxCxE motif to bind RB proteins, impairing their ability to control cell-cycle dependent transcription. E7 disrupts DREAM (Dimerization partner, RB-like, E2F and MuvB), a transcriptional repressor complex that can include p130 or p107, but not pRb, which regulates genes required for cell cycle progression. However, it is not known whether disruption of DREAM plays a significant role in HPV-driven tumorigenesis. In the DREAM complex, LIN52 is an adaptor that binds directly to p130 via an E7-like LxSxE motif. Replacement of the LxSxE sequence in LIN52 with LxCxE (LIN52-S20C) increases p130 binding and partially restores DREAM assembly in HPV-positive keratinocytes and human cervical cancer cells, inhibiting proliferation. Our findings demonstrate that disruption of the DREAM complex by E7 is an important process promoting cellular proliferation by HR-HPV. Restoration of the DREAM complex in HR-HPV positive cells may therefore have therapeutic benefits in HR-HPV positive cancers.