Histone Demethylase JMJD2D Promotes Lung Cancer Progression by Activating Wnt/β-catenin Signaling.

JMJD2D is a histone demethylase implicated in cancer-associated gene regulation, but its role in non-small cell lung cancer (NSCLC) remains incompletely defined. We examined JMJD2D expression and functional effects in patient specimens and lung cancer models. JMJD2D expression was higher in 41 paired NSCLC tissues than in adjacent non-tumor tissues, was greater in stage III-IV than in stage I-II tumors, and was associated with worse overall survival. JMJD2D was also elevated in A549 and H1975 cells relative to HBE cells. shRNA-mediated JMJD2D knockdown reduced CCK-8 and colony-formation readouts and attenuated migration and invasion in both cell lines; it also reduced xenograft tumor growth and lowered MYC, CCND1, MMP2, and MMP9 mRNA and protein levels in tumors. In A549 cells, endogenous co-immunoprecipitation detected JMJD2D and β-catenin in the same complex. PRI-724 or Z-JIB-04 treatment conditions were associated with lower malignancy-associated readouts and lower levels of selected transcripts, without an apparent change in total β-catenin abundance. These findings associate JMJD2D with aggressive clinical and experimental phenotypes in lung cancer and support further investigation of its molecular role and therapeutic relevance.