The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression

Elife. 2022 Nov 16:11:e77072. doi: 10.7554/eLife.77072.

Abstract

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.

Keywords: Capicua; ERF; ETS transcription factors; cancer biology; human; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis
  • DNA-Binding Proteins* / genetics
  • Gene Deletion
  • Humans
  • Male
  • Prostate* / pathology
  • Prostatic Neoplasms* / genetics
  • Repressor Proteins* / genetics
  • Transcription Factors* / genetics

Substances

  • DNA-Binding Proteins
  • ERF protein, human
  • ETV1 protein, human
  • Repressor Proteins
  • Transcription Factors
  • CIC protein, human

Associated data

  • GEO/GSE216732
  • GEO/GSE216318
  • GEO/GSE83653