The aberrant expression of ADAR1 promotes resistance to BET inhibitors in pancreatic cancer by stabilizing c-Myc.

Pancreatic cancer is a malignant tumor with the worst prognosis worldwide. This cancer type requires new insight to help with diagnosis and, eventually, treatment. Adenosine deaminases acting on RNA 1 (ADAR1) is reportedly overexpressed in many types of tumors, such as lung, liver, breast, and esophageal cancers. However, the biological significance and specific mechanism of ADAR1 in pancreatic cancer have not been explored. In this study, we reveal that the expression level of ADAR1 is significantly up-regulated in pancreatic cancer tissues. We also find that highly expressed ADAR1 is closely associated with poor prognosis in pancreatic cancer specimens. Overexpressed ADAR1 equally increased the growth activity of pancreatic cancer cells in vivo and in vitro. We further demonstrate that ADAR1 stabilizes c-Myc through AKT signaling, which contributes to cancer cell resistance to BET inhibitors in pancreatic cancer cells. Moreover, we reveal that EZH2 regulates ADAR1 expression, and EZH2 and BET inhibitors show synergistic inhibition in pancreatic cancer. Collectively, these findings suggest that ADAR1 could serve as a new diagnostic and prognostic marker for the treatment of pancreatic cancer. AJCR