The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity

Yao Shen, Jasvinder Singh, Bindeshwar Sah, Zhongming Chen, Wootae Ha, Christy Henzler, Tao Su, Lillian Xie, Yibin Deng, Gen Li, Hua Guo, Hanina Hibshoosh, Liang Liu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that mutational inactivation of HR promotes tumorigenesis. To investigate HR mutations in breast cancer, we performed targeted next-generation sequencing using DNA isolated from primary breast cancer tissues. We identified HR somatic mutations in approximately 15% of the patient cohort (n = 85), compared with 23% for BRCA2, 13% for GATA3, 7% for BRCA1, and 3% for PTEN in the same patient cohort. We also found an average 23% HR copy number loss in breast cancers. In support of HR’s antitumor functions, HR reconstitution in HR-deficient human breast cancer cells significantly suppressed tumor growth in orthotopic xenograft mouse models. We further demonstrated that HR’s antitumor activity was at least partly mediated by transcriptional activation of CELF2, a tumor suppressor with RNA-binding activity. Consistent with HR’s histone demethylase activity, pharmacologic inhibition of histone methylation suppressed HR-deficient breast cancer cell proliferation, migration and tumor growth. Taken together, we identified HR as a novel tumor suppressor that is frequently mutated in breast cancer. We also showed that pharmacologic inhibition of histone methylation is effective in suppressing HR-deficient breast tumor growth and progression.

Original languageEnglish (US)
Article number4648
JournalCancers
Volume14
Issue number19
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This work utilized the Molecular Pathology Shared Resource Tissue Bank of the Herbert Irving Comprehensive Cancer Center of Columbia University which is in part funded through the NIH/NCI Cancer Center Support Grant P30CA013696. This work was supported by NIH/NIAMS grant K01AR064315, NIH/NCI R01CA196639, Paint the Town Pink, and Prevent Cancer Foundation.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • CELF2
  • breast cancer
  • epigenetic therapy
  • hairless
  • histone methylation

Fingerprint

Dive into the research topics of 'The Histone Demethylase HR Suppresses Breast Cancer Development through Enhanced CELF2 Tumor Suppressor Activity'. Together they form a unique fingerprint.

Cite this