KDM5D epigenetically represses FERD3L to inhibit tumor growth in male colorectal cancer.

Colorectal cancer (CRC) exhibits higher incidence and worse prognosis in males, yet the underlying molecular mechanisms remain incompletely understood. Epigenetic dysregulation, particularly histone modifications, plays a key role in CRC progression and metastasis. KDM5D, a Y-chromosome-encoded H3K4 demethylase, is frequently downregulated in male-predominant malignancies. Here, we explored the potential tumor-suppressive role of KDM5D and its downstream target FERD3L in male CRC. KDM5D and FERD3L expression were evaluated by immunohistochemistry in tumor and adjacent normal tissues from 60 male CRC patients, with correlations to clinicopathological features and survival analyzed. Functional effects of KDM5D overexpression were assessed in SW480 and HCT116 CRC cell lines using proliferation, colony formation, apoptosis, cell cycle, migration, and invasion assays. In vivo validation was performed in subcutaneous xenograft models. Mechanistic studies included ChIP-qPCR for promoter occupancy and H3K4me3 levels, along with rescue experiments using FERD3L overexpression. KDM5D expression was significantly reduced, while FERD3L was upregulated, in male CRC tumors compared with adjacent normal tissues, showing a strong inverse correlation (P < 0.001). Low KDM5D and high FERD3L levels were associated with advanced stage, lymph node metastasis, and poorer overall survival. KDM5D overexpression inhibited cell proliferation, colony formation, migration, and invasion while promoting apoptosis and G1 arrest in vitro. In vivo, KDM5D upregulation significantly suppressed subcutaneous tumor growth and promoted apoptosis, as confirmed by TUNEL assays. These effects were accompanied by reduced expression of mesenchymal markers (N-cadherin, vimentin) and increased E-cadherin. ChIP-qPCR revealed KDM5D recruitment to the FERD3L proximal promoter with concomitant reduction in H3K4me3 levels upon KDM5D overexpression. FERD3L overexpression partially rescued the suppressive phenotypes induced by KDM5D. KDM5D is recruited to the FERD3L promoter and associated with reduced H3K4me3 marks, correlating with transcriptional repression of FERD3L in male CRC. This axis is linked to the suppression of malignant progression and invasiveness in male CRC cells. These findings suggest a potential epigenetic mechanism contributing to sex-biased CRC behavior, warranting further validation in larger cohorts and functional studies of catalytic dependency.