GRIM-19 Restores Cervical Cancer Cell Senescence by Repressing hTERT Transcription

High telomerase activity promotes tumor growth by stabilizing damaged chromosomes and their mitotic replication. Overactivation of telomerase activity has been reported in cervical cancer, a malignancy caused by high-risk human papillomaviruses (HR-HPVs). The HR-HPV E6 can activate hTERT promoter by interacting with E6AP or other binding proteins and by stabilizing the interaction between hTERT and E6AP. GRIM-19 is a novel tumor suppressor that affects multiple targets in a cell to regulate growth. We have previously reported the interaction of GRIM-19 with 18E6 and E6AP to disrupt the E6/E6AP complex and increase the autoubiquitination of E6AP. In this study, we characterized the interaction of GRIM-19 with 16E6 (an oncoprotein produced by HPV16) and identified the binding sites that mediate this interaction. We also found that GRIM-19 expression in cervical cancer cells could inhibit telomerase activity by inhibiting the transactivation of the hTERT promoter by E6, thereby promoting cervical cancer cell senescence. Moreover, we identified a negative correlation between GRIM-19 and hTERT expression in cervical cancer tissues. Suppression of GRIM-19 and induction of hTERT levels were associated with lymph node metastasis, advanced clinical stage, and poor prognosis. This study identified another important novel antitumor molecular link associated with GRIM-19 in the tumorigenesis.