EVI1 overexpression promotes ovarian cancer progression by regulating estrogen signaling

Mol Cell Endocrinol. 2021 Aug 20:534:111367. doi: 10.1016/j.mce.2021.111367. Epub 2021 Jun 17.

Abstract

High-grade serous ovarian cancer (HGSOC) is characterized by TP53 mutation and somatic copy number alterations (SCNAs). Here we show that the oncogenic transcription factor EVI1 (ecotropic viral integration site-1) is amplified and overexpressed up to 30% of 1640 HGSOC cases in The Cancer Genome Atlas (TCGA). Functionally, EVI1 promotes proliferation/invasion in vitro and tumor growth of xenograft model in vivo. Importantly, we discover that EVI1 regulates estrogen signaling by directly activating ESR1 (estrogen receptor 1) transcription determined by the ChIP and luciferase assay. Interestingly, EVI1 and ESR1 share common regulatory targets as indicated by the analysis of ChIP-Seq data. EVI1 and ESR1 collaborate in the regulation of some estrogen receptor-regulated genes. Furthermore, EVI1 drives tumor aggressiveness partially by regulating estrogen signaling. Estrogen enhances the proliferation, invasion and xenograft growth of ovarian cancer cells. Importantly, estrogen can rescue the inhibition of proliferation, invasion and xenograft growth induced by silencing EVI1. These findings suggest that EVI1 functions as a novel regulator of the estrogen signaling network in ovarian cancer.

Keywords: ESR1; EVI1; Estrogen signaling; Ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Cystadenoma, Serous / genetics
  • Cystadenoma, Serous / metabolism
  • Cystadenoma, Serous / pathology*
  • Disease Progression
  • Estrogen Receptor alpha / genetics*
  • Estrogens / metabolism
  • Female
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MDS1 and EVI1 Complex Locus Protein / genetics*
  • Mice
  • Neoplasm Grading
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Signal Transduction
  • Up-Regulation*

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • MDS1 and EVI1 Complex Locus Protein
  • MECOM protein, human