Control of Breast Cancer Pathogenesis by Histone Methylation and the Hairless Histone Demethylase

Megan H. Trager, Bindeshwar Sah, Zhongming Chen, Liang Liu

Research output: Contribution to journalReview articlepeer-review

9 Scopus citations


Breast cancer is a highly heterogeneous disease, encompassing many subtypes that have distinct origins, behaviors, and prognoses. Although traditionally seen as a genetic disease, breast cancer is now also known to involve epigenetic abnormalities. Epigenetic regulators, such as DNA methyltransferases and histone-modifying enzymes, play essential roles in gene regulation and cancer development. Dysregulation of epigenetic regulator activity has been causally linked with breast cancer pathogenesis. Hairless (HR) encodes a 130-kDa transcription factor that is essential for development and tissue homeostasis. Its role in transcription regulation is partly mediated by its interaction with multiple nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors, and vitamin D receptor. HR has been studied primarily in epidermal development and homeostasis. Hr-mutant mice are highly susceptible to ultraviolet- or carcinogen-induced skin tumors. Besides its putative tumor suppressor function in skin, loss of HR function has also been implicated in increased leukemia susceptibility and promotes the growth of melanoma and brain cancer cells. HR has also been demonstrated to function as a histone H3 lysine 9 demethylase. Recent genomics studies have identified HR mutations in a variety of human cancers, including breast cancer. The anticancer function and mechanism of action by HR in mammary tissue remains to be investigated. Here, we review the emerging role of HR, its histone demethylase activity and histone methylation in breast cancer development, and potential for epigenetic therapy.

Original languageEnglish (US)
Article numberbqab088
JournalEndocrinology (United States)
Issue number8
StatePublished - Aug 1 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health/National Cancer Institute (NIH/NCI grant No. R01CA196639), the NIH/Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS grant No. K01AR064315), the Karl Potach Foundation, and the Eagle s Telethon Postdoctoral award (to B.S.). American Heart Association (AHA grant No. 18IPA34110189 to Z.C.).

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.


  • breast cancer
  • hairless
  • histone demethylase
  • histone methylation
  • oncogenesis


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