Pharmacological enhancement of 20S proteasome-mediated degradation exposes a vulnerability in human papillomavirus (HPV)-driven cervical cancer

Abstract Abstract: Despite the availability of prophylactic vaccines against human papillomavirus (HPV), infection and subsequent cervical cancer remain a significant global health problem. HPV viral oncoproteins E6 and E7 drive oncogenesis, in part through disruption of cell growth control pathways via degradation of the tumor suppressors p53 and pRB, respectively. These proteins contain intrinsically disordered regions that enable interactions with multiple cellular targets but also complicate the development of conventional therapeutics. While these proteins have previously been associated with a ubiquitin-dependent clearance mechanism through the 26S proteasome, we show that these HPV viral proteins can be degraded in a ubiquitin-independent method through the 20S proteasome alone. We also show that the small molecule-enhancement of this protease reduces HPV E6 and E7 protein levels across high-risk strains of the virus in a proteasome-dependent and transcription-independent manner. 20S proteasome activation suppressed HPV-driven phenotypes, including reduced proliferation and restoration of cell-cycle regulatory signaling. Whole cell proteomic analysis revealed remodeling of cancer-associated pathways including shifts consistent with reduced proliferative and oncogenic metabolic signaling. Collectively, these findings identify a previously unrecognized vulnerability of HPV oncoproteins and establish 20S proteasome activation as a potential therapeutic strategy for HPV-associated cancers.