Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

J Biol Chem. 2016 Apr 29;291(18):9690-9. doi: 10.1074/jbc.M115.707612. Epub 2016 Mar 7.

Abstract

ARID1A is a tumor suppressor gene that belongs to the switch/sucrose non-fermentable chromatin remodeling gene family. It is mutated in many types of human cancer with the highest frequency in endometrium-related ovarian and uterine neoplasms including ovarian clear cell, ovarian endometrioid, and uterine endometrioid carcinomas. We have previously reported that mutations in the promoter of human telomerase reverse transcriptase (TERT) rarely co-occur with the loss of ARID1A protein expression, suggesting a potential role of ARID1A in telomere biology. In this study, we demonstrate that ARID1A negatively regulates TERT transcriptional regulation and activity via binding to the regulatory element of TERT and promotes a repressive histone mode. Induction of ARID1A expression was associated with increased occupancy of SIN3A and H3K9me3, known transcription repressor and histone repressor marks, respectively. Thus, loss of ARID1A protein expression caused by inactivating mutations reactivates TERT transcriptional activity and confers a survival advantage of tumor cells by maintaining their telomeres.

Keywords: ARID1A; chromatin remodeling; ovarian cancer; telomerase reverse transcriptase (TERT); telomere; tumor suppressor gene.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Gene Expression Regulation, Enzymologic*
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Mutation*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Telomerase / biosynthesis*
  • Telomerase / genetics
  • Telomere Homeostasis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • ARID1A protein, human
  • Histones
  • Nuclear Proteins
  • Repressor Proteins
  • SIN3A transcription factor
  • Transcription Factors
  • Tumor Suppressor Proteins
  • TERT protein, human
  • Telomerase