Endometrial cancer is one of the most common cancers of the female reproductive system. CHD4, a core subunit of the nucleosome remodeling and deacetylation (NuRD) complex, is frequently mutated in these patients. However the role it plays in promoting endometrial tumorigenesis is poorly understood. Here, we use genetic engineering approaches to modulate CHD4 expression levels and functionally evaluate hot spot mutations R975H and R1162W. We find that CHD4 depletion induces up-regulation of the cancer stem cell (CSC) marker CD133. This CSC phenotype was verified functionally by invasion ability, spheroid formation, and tumorigenicity in vivo. While cells expressing mutated CHD4 did not display impaired CHD4 DNA recruitment or NuRD complex formation, the mutations did reduce the stability of CHD4 protein to phenocopy CHD4 depletion. Consistently, patients with mutant CHD4 showed overexpression of CD133. Network analysis indicated activation of the TGFβ signaling pathway may drive this CSC phenotype, and chemical blockade of TGFβ abrogated the ability CHD4 knockdown cells to form spheroids. Taken together, these results indicate that mutations in CHD4 can promote endometrial tumorigenesis by increasing CSC character through TGFβ signaling pathway.
Keywords: CD133; CHD4; TGFβ; cancer stem cell; endometrial cancer.