The hairless (HR) gene encodes a transcription factor with histone demethylase activity that is essential for development and tissue homeostasis. Previous studies suggest that HR possesses antitumor activity in skin cancer models. Surveying human cancer genomics datasets identified frequent HR missense mutations or deletions in various human malignancies including breast cancers, suggesting that HR might function as a tumor suppressor in cancer development. By targeted sequencing, we identified HR mutations in approximately 29% of human breast cancer tissues (n=85), compared to 33% for BRCA2 and 17% for BRCA1 in the same sample cohort. Digital PCR assays also revealed frequent HR copy number loss across breast cancer subtypes. To further define HR’s putative tumor suppressor function in breast cancer and its mechanism of action, we reconstituted HR expression in HR-deficient human breast cancer cells. HR re-expression significantly suppressed tumor growth and metastasis in orthotopic xenograft mouse models. This antitumor activity of HR in breast cancer cells was partly associated with transcriptional activation of the CELF2 tumor suppressor gene, a new HR-regulated gene identified by RNA-seq studies. Consistent with HR’s H3K9 demethylase activity, pharmacological inhibition of H3K9 methylation inhibited HR-deficient breast cancer cell proliferation and migration. Taken together, these studies demonstrate that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to reduce HR-deficient breast cancer cell growth and survival. methylation inhibited HR-deficient breast cancer cell proliferation and migration in vitro, and tumor growth and metastasis in xenograft models. Taken together, these studies suggest that HR is a novel tumor suppressor, and pharmacological inhibition of H3K9 methylation may be explored to treat HR-deficient breast cancers.

Citation Format: Liang Liu, Yao Shen, Jasvinder Singh, Bindy Sah, Zhongming Chen, Christine Henzler, Wootae Ha, Tao Su, Hanina Hibshoosh. The histone demethylase hairless functions as a tumor suppressor gene in breast cancer development [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-04.