ASH2L Acts As a Co-Activator of ERα to Participate in the Promotion of Endometrial Cancer Progression

Abstract

Background: Estrogen-ERα signaling is an oncogenic pathway plays a crucial role in endometrial carcinogenesis. However, modulation of ERα action in Endometrial cancer (ECa) remains to be elusive. Absent, small or homeotic 2-like protein (ASH2L) is a core component of multimeric histone methyltransferase complex, which is involved in maintenance the active chromatin states. What is the function of ASH2L on modulation of E2-ERα induced transactivation in ECa needs to be further understood. Methods: Immunoprecipitation, Immunofluorescence assay, luciferase assay, quantitative RT-PCR, and western blot were performed to investigate how ASH2L regulates the transcriptional activity of ERα. ChIP assay was performed to determine the recruitment of ASH2L to cis-regulatory elements. Lentiviral infection, colony formation, transwell experiments, and mice xenograft experiments were performed to evaluate the function of ASH2L on cell growth and migration. Findings: Our study demonstrated that ASH2L was highly expressed in ECa samples, and the higher expression of ASH2L is positively correlated with the poor prognosis. ASH2L associates with ERα and upregulates ERα-induced transactivation in ECa cells. ASH2L is recruited to cis -regulatory elements at ERα regulated gene, thereby modulating histone H3K4me3 and H3K27me3 levels, to maintain the active transcription. ASH2L depletion suppresses cell growth and migration in ECa. Interpretation: Our findings suggest that ASH2L associates with ERα to be involved in regulation of ERα-induced transactivation. ASH2L participates in promotion of ECa progression. Funding Statement: This study was supported by National Natural Science Foundation of China [31871286 for Yue Zhao, 81872015 for Chunyu Wang, 31701102 for Shengli Wang, 81702800 for Renlong Zou, 81502438 for Tingting Zhou, 81902889 for Wensu Liu]. Declaration of Interests: The authors declare no conflict of interests. Ethics Approval Statement: All procedures of animal experiments have been carried out in compliance with ethical regulations approved by the Animal Ethics Committee of China Medical University. This study was approved by the Ethics Committee of the Medical Faculty of the China Medical University.