Abstract 1749: DRAK1 suppresses inflammation-induced cervical cancer progression by targeting TRAF6 protein

Cervical cancer is a major cause of mortality in women worldwide and strongly associated with persistent infection with high-risk (HR) human papillomavirus (HPV), mainly HPV16 and HPV18. Most HPV viruses can be cleared by the immune system, and a preventive and effective vaccine against HPV infection decreases the development of cervical cancer. The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) specifically decreases the stability of the TRAF6 protein via an autophagy-mediated degradation pathway by interfering with the homo-oligomerization of TRAF6, eventually suppressing tumor growth and metastasis in inflammation-associated advanced cervical cancer cells. DRAK1 bounds directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1β signaling-associated pathway and pro-inflammatory cytokine production. DRAK1 knockdown accelerated cervical cancer tumorigenesis and metastasis whereas DRAK1 overexpression suppressed that phenomenon. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel potential biomarker and novel therapeutic target for treatment of TRAF6-associated advanced cervical cancers. [This work was supported by National RD 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1749.