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

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.

• Authors: Chiujung Yang, Kazuhiro Ikeda, Kuniko Horie-Inoue, Wataru Sato, Kosei Hasegawa, Satoru Takeda, Atsuo Itakura, Satoshi Inoue
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 548 Pg. 204-210 (04 09 2021) ISSN: 1090-2104 [Electronic] United States
• PMID: 33647797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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