ALDH1A3 contributes to tumorigenesis in high-grade serous ovarian cancer by epigenetic modification

Abstract

High-grade serous ovarian cancer (HGSOC) is the most lethal histotype of ovarian cancer due to its unspecific symptoms in part. ALDH1A3 (aldehyde dehydrogenase 1 family member A3) is a key enzyme for acetyl-CoA production involving aggressive behaviors of cancers. However, ALDH1A3's effects and molecular mechanisms in HGSOC remain to be clarified. Using RNA-seq and publicly available datasets, ALDH1A3 was found to be highly expressed in HGSOC, and associated with poor survival. Knockdown of ALDH1A3 prevented HGSOC tumorigenesis and enhanced cell sensitivity to paclitaxel or cisplatin. ALDH1A3 expression in HGSOC cells was found to be increased by hypoxia, but decreased by HIF-1α inhibitor KC7F2. The dual-luciferase reporter assay showed that the increased transcriptional activity of ALDH1A3 induced by HIF-1α overexpression was reduced by KC7F2. In addition, PITX1 (paired like homeodomain 1) was identified to be inhibited by ALDH1A3 knockdown, and PITX1 depletion inhibited cell proliferation. The mechanistic studies showed that ALDH1A3 knockdown reduced the acetylation of histone 3 lysine 27 (H3K27ac). Treatment of exogenous acetate with NaOAc or inhibition of histone deacetylase with Pracinostat increased H3K27ac and PITX1 levels. CHIP assay demonstrated a significant enrichment of H3K27ac at the PITX1 promoter, and ALDH1A3 knockdown reduced the binding between H3K27ac and PITX1. Taken together, our data suggest that ALDH1A3, transcriptional activated by HIF-1α, promotes tumorigenesis and decreases chemosensitivity by increasing H3K27ac of PITX1 promoter in HGSOC.