Sexually Dimorphic RNA Helicase DDX3Y, But Not DDX3X, Plays a Potential Tumor-Suppressive Role in Colorectal Carcinogenesis in Males.

Beyond its role in sex determination, the Y chromosome contains genes that regulate transcription, translation, and protein stability, thereby contributing to the pathogenesis of various male-specific diseases, including cancer. Although sex significantly influences cancer incidence and outcomes, the molecular mechanisms underlying these differences remain poorly understood. These disparities are particularly evident in colorectal cancer (CRC), where men experience higher incidence, metastasis, and mortality rates. Here, we provide the first evidence that the sexually dimorphic RNA helicase DDX3Y (DEAD-box helicase 3 Y-linked), but not its X-linked homolog DDX3X, is significantly downregulated in tumor tissues from male CRC patients (n = 22). Overexpression of DDX3Y suppressed CRC cell proliferation, invasion, and colony formation while promoting apoptosis (p < 0.01). Conversely, siRNA-mediated depletion of DDX3Y, but not DDX3X, enhanced proliferation, invasion, and colony formation in normal colorectal mucosal cells (p < 0.01). Mechanistically, DDX3Y regulated the expression of key genes involved in cell growth and invasion, including KRAS, PIK3CA, PTEN, Snail, TCF7L1, and E-cadherin, whereas DDX3X had no significant effect on these targets. Collectively, these findings identify DDX3Y as a potential male-specific tumor suppressor in CRC and support further investigation of its prognostic and therapeutic potential in colorectal cancer.