ERR alpha Up-Regulates Invadopodia Formation by Targeting HMGCS1 to Promote Endometrial Cancer Invasion and Metastasis

Estrogen-related receptor alpha (ERR alpha) plays an important role in endometrial cancer (EC) progression. However, the biological roles of ERR alpha in EC invasion and metastasis are not clear. This study aimed to investigate the role of ERR alpha and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) in regulating intracellular cholesterol metabolism to promote EC progression. ERR alpha and HMGCS1 interactions were detected by co-immunoprecipitation, and the effects of ERR alpha/HMGCS1 on the metastasis of EC were investigated by wound-healing and transwell chamber invasion assays. Cellular cholesterol content was measured to verify the relationship between ERR alpha and cellular cholesterol metabolism. Additionally, immunohistochemistry was performed to confirm that ERR alpha and HMGCS1 were related to EC progression. Furthermore, the mechanism was investigated using loss-of-function and gain-of-function assays or treatment with simvastatin. High expression levels of ERR alpha and HMGCS1 promoted intracellular cholesterol metabolism for invadopodia formation. Moreover, inhibiting ERR alpha and HMGCS1 expression significantly weakened the malignant progression of EC in vitro and in vivo. Our functional analysis showed that ERR alpha promoted EC invasion and metastasis through the HMGCS1-mediated intracellular cholesterol metabolism pathway, which was dependent on the epithelial-mesenchymal transition pathway. Our findings suggest that ERR alpha and HMGCS1 are potential targets to suppress EC progression.

Automated summary

This study investigates the role of ERR alpha and HMGCS1 in promoting intracellular cholesterol metabolism for endometrial cancer progression, and suggests that they could be potential targets to suppress EC progression.