Transcriptional suppression of Dicer by HOXB‐AS3/EZH2 complex dictates sorafenib resistance and cancer stemness

Sorafenib is a multikinase inhibitor for the standard treatment of advanced liver cancer patients. However, acquired resistance to sorafenib is responsible for a poor prognosis. Therefore, uncovering the molecular mechanisms underlying sorafenib sensitization can provide biomarkers for sorafenib treatment and improve sorafenib activity in a precise medication. Here, we report that epigenetic suppression of Dicer by the HOXB‐AS3/EZH2 complex is responsible for sorafenib resistance. We observed that Dicer expression is inversely correlated with EZH2 levels, HOXB‐AS3 expression, sorafenib resistance, and cancer stem cell properties in liver cancer patients. Furthermore, ectopic expression of Dicer induced liver cancer cells resensitization to sorafenib. Mechanistically, we found HOXB‐AS3 physically interacts with EZH2 and recruits EZH2 to the Dicer promoter, resulting in epigenetic suppression of Dicer expression. These findings reveal that HOXB‐AS3/EZH2 complex–mediated Dicer suppression plays an important role in sorafenib resistance and cancer stemness and provide potential therapeutic strategies for diagnosing and treating liver cancer patients.