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

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.

SUBMITTER: Shen Y

PROVIDER: S-EPMC9564370 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Shen Yao Y Singh Jasvinder J Sah Bindeshwar B Chen Zhongming Z Ha Wootae W Henzler Christine C Su Tao T Xie Lillian L Deng Yibin Y Li Gen G Guo Hua H Hibshoosh Hanina H Liu Liang L

Cancers 20220924 19

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 wi ...[more]

PMID: 36230572

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Project description:BACKGROUND:The tumor suppressor actions of hexamethylene bis-acetamide (HMBA)-inducible protein 1 (HEXIM1) in the breast, prostate, melanomas, and AML have been reported by our group and others. Increased HEXIM1 expression caused differentiation and inhibited proliferation and metastasis of cancer cells. Historically, HEXIM1 has been experimentally induced with the hybrid polar compound HMBA, but HMBA is a poor clinical candidate due to lack of a known target, poor pharmacological properties, and unfavorable ADMETox characteristics. Thus, HEXIM1 induction is an intriguing therapeutic approach to cancer treatment, but requires better chemical tools than HMBA. METHODS:We identified and verified KDM5B as a target of HEXIM1 inducers using a chemical proteomics approach, biotin-NeutrAvidin pull-down assays, surface plasmon resonance, and molecular docking. The regulation of HEXIM1 by KDM5B and KDM5B inhibitors was assessed using chromatin immunoprecipitation assays, RT-PCR, western blotting, and depletion of KDM5B with shRNAs. The regulation of breast cancer cell phenotype by KDM5B inhibitors was assessed using western blots, differentiation assays, proliferation assays, and a mouse model of breast cancer metastasis. The relative role of HEXIM1 in the action of KDM5B inhibitors was determined by depleting HEXIM1 using shRNAs followed by western blots, differentiation assays, and proliferation assays. RESULTS:We have identified a highly druggable target, KDM5B, which is inhibited by small molecule inducers of HEXIM1. RNAi knockdown of KDM5B induced HEXIM1 expression, thus validating the specific negative regulation of tumor suppressor HEXIM1 by the H3K4me3/2 demethylase KDM5B. Known inhibitors of KDM5B were also able to induce HEXIM1 expression, inhibit cell proliferation, induce differentiation, potentiate sensitivity to cancer chemotherapy, and inhibit breast tumor metastasis. CONCLUSION:HMBA and 4a1 induce HEXIM1 expression by inhibiting KDM5B. Upregulation of HEXIM1 expression levels plays a critical role in the inhibition of proliferation of breast cancer cells using KDM5B inhibitors. Based on the novel molecular scaffolds that we identified which more potently induced HEXIM1 expression and data in support that KDM5B is a target of these compounds, we have opened up new lead discovery and optimization directions.

Dataset Information

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

Publications

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

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