Transcriptomic analysis of hormone-sensitive patient-derived endometrial cancer spheroid culture defines Efp as a proliferation modulator

Biochem Biophys Res Commun. 2021 Apr 9:548:204-210. doi: 10.1016/j.bbrc.2021.02.066. Epub 2021 Feb 26.

Abstract

Estrogen-responsive endometrial cancer (EC) is prevalent in uterine cancer. Its precise molecular mechanisms remain to be elucidated partly because of limited availability of estrogen-sensitive EC models recapitulating clinical pathophysiology. We previously established EC patient-derived cancer cell (EC-PDC) spheroid culture with high expression of estrogen receptor α (ERα). Using this EC-PDC, we study the transcriptional regulation and function of estrogen-responsive finger protein (Efp), a prototypic tripartite motif (TRIM) protein that modulates protein degradation and RNA processing. Intense estrogen-dependent EFP mRNA induction and high ERα occupancy to EFP estrogen responsive element (ERE) were observed in EC-PDC. Luciferase reporter gene assay showed that the ERE facilitates EFP transcriptional activity estrogen-dependently. siRNA-mediated Efp silencing in EC-PDC resulted in suppressed spheroid proliferation and altered gene expression profile, featuring downregulation of genes related to cell cycle (e.g., CDK6) and inflammation/immune responses (e.g., IL10RA, IL26, and IL6ST) while unaffected expression of cancer stemness-related markers. Taken together, EC-PDC spheroid culture is a powerful EC tool that enables to dissect Efp-mediated ERα signaling pathways as an estrogen-sensitive EC model. This study provides an insight into alternative EC therapeutic strategies targeting ERα-Efp axis.

Keywords: Cyclin dependent kinase 6 (CDK6); Endometrial cancer; Estrogen; Estrogen-responsive finger protein (Efp); Patient-derived cancer cell (PDC).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Endometrial Neoplasms / genetics*
  • Endometrial Neoplasms / immunology
  • Endometrial Neoplasms / pathology*
  • Estrogen Receptor alpha / metabolism
  • Estrogens / pharmacology*
  • Female
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Spheroids, Cellular / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic / drug effects
  • Tripartite Motif Proteins / genetics
  • Tripartite Motif Proteins / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • ESR1 protein, human
  • Estrogen Receptor alpha
  • Estrogens
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM25 protein, human
  • Ubiquitin-Protein Ligases