Yi Huang, MD, PhD
Magee-Womens Research Institute, A406
Breast cancer; epigenetics; histone modification, gene silencing; estrogen receptor
Dr. Huang’s research interests focus on the role of histone modification in breast cancer development. There is a growing body of evidence to suggest that changes in the activity of chromatin-modifying enzymes contribute to uncontrolled breast cell proliferation and tumorigenesis. Our main research objective is to define in depth the mechanisms and biological consequences of functional interplay between key histone enzymes in breast cancer growth and metastasis. We are also interested in identifying novel, small molecule reagents that act as selective inhibitors of important chromatin-modifying enzymes to target more specifically the small regions of chromatin and the subset of genes that are associated with most prominent alterations in the breast cancer genome. Our recent work demonstrated that activities of histone lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are functionally linked in breast cancer, especially in triple negative breast cancer (TNBC). Clinically, TNBC is more aggressive, and distant visceral metastases are more common, in comparison with non-TNBC counterparts. TCGA data suggest that LSD1 is highly expressed in TNBC. We demonstrated that LSD1 inhibition in combination with HDAC inhibition displays superior synergy in blocking growth and inducing expression of aberrently silenced genes in TNBC cells. We are investigating the precise mechanisms contributing to orchestrated crosstalk between histone modifiers in breast cancer and determining how the dysregulated interaction of histone-modifying enzymes leads to aberrant gene silencing and the aggressive phenotype of TNBC. We are also studying whether targeting LSD1/HDAC crosstalk by novel inhibitors is more efficacious in hindering TNBC growth than current strategies and thus represents a novel targeted therapy for this devastating disease.
Lysine-specific demethylase 2 (LSD2), a homolog of LSD1, was recently identified. LSD1 and LSD2 share significant amino acid sequence homology in the amine oxidase domain, and both enzymes demethylate lysine 4 on histone 3 in a FAD-dependent manner. However, LSD1 and LSD2 clearly form different chromatin-remodeling complexes and bind to distinct genomic elements of target genes. LSD2 is highly expressed in invasive breast cancer. Our recent study showed that inhibition of LSD2 reduces breast cancer cell motility and colony formation, attenuates global DNA methylation, and enhances antitumor efficacy of DNMT inhibitor. We therefore hypothesize that LSD2 plays an important role in breast tumor progression/metastasis, and that inhibition of LSD2 blocks breast tumor cell growth/metastasis and enhances efficacy of targeted epigenetic drug therapies. Our ongoing study is to understand the mechanisms underlying LSD2 regulation on breast cancer tumorigenesis and elucidate the role of LSD2 in epigenetic drug therapy and chemoprevention of human breast cancer.
- Katz TA, Vasilatos SV, Oesterreich S, Davidson, NE, Huang Y. Inhibition of histone demethylase, LSD2 (KDM1B), attenuates DNA methylation and increases sensitivity to DNMT inhibitor-induced apoptosis in breast cancer cells. Breast Cancer Res. Treat., 146(1):99-108, 2014. PubMed Link
- Vasilatos SV, Katz TA, Oesterreich S, Wan Y, Davidson, NE, Huang Y. Crosstalk between Lysine-specific Demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells. Carcinogenesis, 34(6):1196-207, 2013. PubMed Link
- Zhu Q, Jin L, Casero RA, Davidson NE, Huang Y. Role of ornithine decarboxylase in regulation of estrogen receptor alpha expression and growth in human breast cancer cells. Breast Cancer Res. Treat., 136:57-66, 2012. PubMed Link
- Huang Y, Vasilatos S, Boric L, Shaw PW, Davidson NE. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Res. Treat., 131:777-89, 2012. PubMed Link
- Jin K, Kong X, Shah T, Penet MF, Wildes F, Sgroi DC, Ma XJ, Huang Y, Kallioniemi A, Landberg G, Bieche I, Wu X, Lobie PE, Davidson NE, Bhujwalla ZM, Zhu T, Sukumar S. HOXB7 renders breast cancer resistant to tamoxifen through activation of the EGFR pathway. Proc Natl Acad Sci USA. 109(8):2736-41, 2012. PubMed Link
- Huang Y, Nayak S, Jankowitz R, Davidson NE, Oesterreich S. Epigenetics in breast cancer-what's new? Breast Cancer Res., 13(6):225, 2011. PubMed Link
- Huang Y, Stewart TM, Wu Y, Baylin SB, Marton LJ, Woster PM, Casero RA. Novel oligoamine analogues inhibit lysine-specific demethylase 1 (LSD1) and induce re-expression of epigenetically silenced genes. Clin. Cancer Res., 15:7217-28, 2009. PubMed Link
- Huang Y, Greene E, Stewart TM, Goodwin AC, Baylin SB, Woster PM, Casero RA. Inhibition of the lysine specific demethylase, LSD1, by novel polyamine analogues results in re-expression of aberrantly silenced genes. Proc Natl Acad Sci USA, 104(19): 8023-8028, 2007. PubMed Link
- Huang Y, Keen JC, Pledgie A, Marton LJ, Zhu T, Sukumar S, Park BH, Blair BG, Brenner K, Casero RA, Davidson NE. Polyamine analogues down-regulate estrogen receptor alpha expression in human breast cancer cells. J. Biol. Chem., 281(28): 19055-19063, 2006. PubMed Link
- Huang Y, Hager ER, Phillips DL, Dunn VR, Hacker A, Frydman B, Kink JA, Valasinas AL, Reddy VK, Marton LJ, Casero RA, Davidson NE. A novel polyamine analog inhibits growth and induces apoptosis in human breast cancer cells. Clin. Cancer. Res., 9: 2769-2777, 2003. PubMed Link