Nuclear-translocation of ACLY induced by obesity-related factors enhances pyrimidine metabolism through regulating histone acetylation in endometrial cancer

Endometrial cancer (EC) is becoming one of the most common gynecologic malignancies. Lipid metabolism is a hallmark feature of cancers. The molecular mechanisms underlying lipid metabolism in EC remain unclear. In this study, we revealed that many lipid metabolism-related genes were aberrantly expressed in endometrial cancer tissues, especially ACLY. Upregulated ACLY promoted EC cell proliferation and colony formation, and attenuated apoptosis. Mechanistically, cotreatment with obesity-related factors (estradiol, insulin and leptin) promoted nuclear translocation of ACLY through Akt-mediated phosphorylation of ACLY at Ser455. Nuclear-localized ACLY increased histone acetylation levels, thus resulting in upregulation of pyrimidine metabolism genes, such as DHODH. Moreover, STAT3 altered the ACLY expression at the transcriptional level via directly binding to its promoter region. In conclusion, our findings clarify the roles and mechanisms of ACLY in endometrial cancer and ACLY could link obesity risk factors to the regulation of histone acetylation. We believe that novel therapeutic strategies for EC can be designed by targeting the ACLY axis.