Inactivating ARID1A tumor suppressor enhances TERT transcription and maintains telomere length in cancer cells

Yohan Suryo Rahmanto, Jin Gyoung Jung, Ren Chin Wu, Yusuke Kobayashi, Christopher M Heaphy, Alan Keith Meeker, Tian-Li Wang, Ie Ming Shih

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)9690-9699
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number18
DOIs
StatePublished - 2016

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Telomerase
Telomere
Transcription
Reverse Transcription
Tumors
Cells
Histones
Histone Code
Genes
Endometrioid Carcinoma
Neoplasms
Uterine Neoplasms
Mutation
Chromatin Assembly and Disassembly
Endometrium
Tumor Suppressor Genes
Ovarian Neoplasms
Chromatin
Sucrose
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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Inactivating ARID1A tumor suppressor enhances TERT transcription and maintains telomere length in cancer cells. / Suryo Rahmanto, Yohan; Jung, Jin Gyoung; Wu, Ren Chin; Kobayashi, Yusuke; Heaphy, Christopher M; Meeker, Alan Keith; Wang, Tian-Li; Shih, Ie Ming.

In: Journal of Biological Chemistry, Vol. 291, No. 18, 2016, p. 9690-9699.

Research output: Contribution to journalArticle

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AU - Jung, Jin Gyoung

AU - Wu, Ren Chin

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AU - Heaphy, Christopher M

AU - Meeker, Alan Keith

AU - Wang, Tian-Li

AU - Shih, Ie Ming

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AB - 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.

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