ERCC6L in human cancers: oncogenic functions, molecular mechanisms, and clinical implications as a prognostic...

Excision repair cross-complementation group 6-like (ERCC6L), also known as PICH, is a centromere-associated SNF2 family ATPase that functions as a DNA helicase essential for mitotic chromosome segregation. Emerging evidence has established its significant oncogenic role across a broad spectrum of human malignancies. This review synthesizes current knowledge on the expression landscape, oncogenic functions, molecular mechanisms, and clinical significance of ERCC6L in cancer. Pan-cancer analyses consistently demonstrate that ERCC6L is frequently overexpressed in most tumor types compared to normal tissues, driven by mechanisms such as DNA amplification and promoter hypomethylation. This upregulation strongly correlates with aggressive clinicopathological features, including advanced tumor stage, metastasis, and poor patient prognosis across cancers like breast cancer, hepatocellular carcinoma, lung adenocarcinoma, and gastric cancer. Functionally, ERCC6L acts as a potent driver of malignant phenotypes by promoting uncontrolled proliferation through cell cycle acceleration, exerting anti-apoptotic effects, and enhancing invasion and metastasis via epithelial-mesenchymal transition. Mechanistically, ERCC6L operates at the nexus of multiple cancer pathways. It interacts with key mitotic regulators including PLK1, FOXM1, and KIF4A to govern cell cycle progression, activates pro-survival signaling cascades such as PI3K/AKT and NF-κB, and drives metastasis via PJA2-mediated p53 ubiquitination in lung adenocarcinoma. Furthermore, ERCC6L promotes metabolic reprogramming by stabilizing HIF-1α or transactivating PLK1 to drive aerobic glycolysis, and modulates DNA damage response, linking it to radio- and chemoresistance. Emerging evidence also connects ERCC6L to an immunosuppressive tumor microenvironment, with associations including Th2 cell infiltration, macrophage polarization, and reduced immune infiltration in HRD-high tumors, suggesting potential as a predictive biomarker for immunotherapy. The consistent association with aggressive tumor behavior positions ERCC6L as a valuable prognostic biomarker and a promising therapeutic target. Preclinical studies demonstrate that ERCC6L inhibition suppresses tumor growth and enhances treatment efficacy; however, current evidence is limited to in vitro and xenograft models, and substantial further validation is required before clinical translation.