KDM4B/DHX9 promotes chemoresistance in small cell lung cancer through MYCN-driven signaling pathway

Small cell lung cancer (SCLC) is prone to developing chemoresistance, which is associated with epigenetic reprogramming. While LSD1-mediated histone demethylation has been reported, a systematic investigation into the role of histone demethylases in SCLC chemoresistance is lacking. In this study, we established nine chemoresistant cell lines from parental cells via gradual dose escalation and conducted RNA sequencing, followed by linear regression and random effects meta-analysis to identify genes associated with chemoresistance among 23 histone demethylases. We subsequently validated our findings using two neuroendocrine SCLC cell lines and their corresponding chemoresistant counterparts. We identified KDM4B as a key driver of chemoresistance, with immunohistochemical analysis revealing its elevated expression in chemoresistant tissues from SCLC patients, although its association with neuroendocrine subtypes warrants further investigation. KDM4B promoted chemoresistance through the Hedgehog pathway by enhancing cell proliferation and stemness. Mechanistically, KDM4B interacts with DHX9 and corecruits to the MYCN promoter to promote its transcription and activate the Hedgehog signaling pathway. An inhibitor of DHX9 had synergistic antitumor effects with cisplatin and etoposide, and effectively rescued the chemosensitivity of SCLC both in vitro and in vivo. These findings provide valuable insights for future studies aimed at developing therapeutic strategies to overcome chemoresistance in SCLC.