Dependence of p53-deficient cells on the DHX9 DExH-box helicase.

DHX9 is a DExH-box helicase family member with key regulatory roles in a broad range of cellular processes. It participates at multiple levels of gene regulation, including DNA replication, transcription, translation, RNA transport, and microRNA processing. It has been implicated in tumorigenesis and recent evidence suggests that it may be a promising chemotherapeutic target. Previous studies have determined that DHX9 suppression elicits an apoptotic or senescence response by activating p53 signaling. Here, we show that DHX9 inhibition can also have deleterious effects in cells lacking functional p53. Loss of DHX9 led to increased cell death in p53-deficient mouse lymphomas and HCT116 human colon cancer cells, and G0/G1 cell cycle arrest in p53-deficient mouse embryonic fibroblasts. Analysis of mRNA levels for p53 transcriptional targets showed that a subset of p53 targets in the p53-null lymphomas and HCT116 cells were activated despite the absence of functional p53. This implies an alternative pathway of DHX9-mediated activation of cell death and cell cycle arrest in p53-deficient cells and supports the feasibility of targeting DHX9 in p53-deficient tumors.