Synthetic Essentiality of TNFSF10/TRAIL in VHL-Deficient Renal Cell Carcinoma

Renal cell carcinoma (RCC) is among the 10 most common cancers worldwide, constituting approximately 2% of all cancer diagnoses and cancer deaths. Originating from the renal epithelium, RCC accounts for over 90% of cancer in the kidney. The predominant subtype of RCC, known as clear cell renal cell carcinoma (ccRCC), is responsible for most deaths from kidney cancer. One notable genetic factor that contributed to the ccRCC is VHL, which encodes VHL protein. The mutated genes were first identified as underlying the von Hippel Lindau disease. Inactivation of VHL as tumor suppressor genes (TSG) leads to the stabilization of oncogenic hypoxia-inducible factor 1(HIF1) and HIF2. HIF2a plays an essential role in cancer progression, as it promotes gene expression involved in cell survival across multiple signaling pathways. Over the past decades, numerous HIF targets have been identified, which have facilitated the development of therapeutic strategies on ccRCC. In this study, we identified TNFSF10 encodes the tumor necrosis factor (TNF)- related apoptosis-inducing ligand (TRAIL) as a top essential gene upregulated by HIF2a. shRNA-mediated knockdown of TRAIL resulted in reduced cell viability and tumorigenicity. TRAIL facilitates G1/S transition through phosphorylation of p38 MAP kinase. The study also identified a feedback mechanism where sustained TRAIL knockdown led to a decrease in HIF2a levels. Finally, combining HIF2a inhibition with recombinant TRAIL synergistically suppressed 786O cell survival, underscoring the therapeutic potential of dual targeting HIF2a and TRAIL in RCC. This research provides novel insights into the non-apoptotic roles of TRAIL in ccRCC and presents a promising therapeutic strategy for combating this malignancy.