Dr. Huang’s research interests focus on the investigation of epigenetic regulation of gene expression in human breast cancer. In breast cancer, DNA hypermethylation frequently acts in collaboration with abnormal histone modifications leading to decreased chromatin activating marks such as H3K4me and AcH3K9 and increased repressive marks such as H3K9me and H3K27me that result collectively in the aberrant silencing of specific genes such as tumor suppressor genes. Over the last decade, significant progress has been made in identification and characterization of aberrantly silenced genes in breast cancer development and progression. Importantly, epigenetic changes, unlike mutations or loss of chromosomes, are reversible. Therefore, it is possible through treatment to restore normal growth control by reversing epigenetically silenced genes. Our main research objective is to define in depth the mechanisms and biological consequences of functional interplay between epigenetic modifiers in chromatin remodeling and gene transcription in breast cancer. The laboratory is also interested in identifying novel agents in targeting epigenetic alterations in human breast cancer. Our recent work demonstrated that activities of histone lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are intimately linked in breast cancer cells. LSD1 inhibitor in combination with HDAC inhibitor led to enhanced levels of active histone marks such as H3K4me2 and AcH3K9, and displayed synergy in blocking growth of breast cancer cells. Genome wide microarray screening identified a unique subset of genes whose expression was significantly induced by combination treatment with inhibitors of LSD1 and HDAC. We are investigating the genome wide crosstalk between LSD1 and HDACs in breast cancer by using high-throughput approaches. We will also determine if inhibitors of LSD1/HDAC crosstalk are more efficacious in reactivating aberrantly silenced genes and inhibiting tumor growth than current strategies and thus represent a novel targeted therapy for breast cancer.
Recently, a second mammalian FAD dependent histone demethylase, LSD2 (also known as KDM1B or AOF1), has been identified. Amino acid sequence analysis reveals that LSD1 and LSD2 share considerable overall similarity in the amine oxidase domain. Our studies showed that LSD2 possesses the activity to demethylate H3K4 in human breast cancer cells, suggesting the existence of a more sophisticated FAD-dependent histone demethylase family whose members play a role in chromatin remodeling and transcription regulation in breast cancer. Despite structural and catalytic similarities, little is known about the epigenetic activity and biological function of LSD2 in breast cancer. LSD2 is likely to be part of chromatin-remodeling complexes that are different from those involving the LSD1/CoREST/HDAC. We are examining the epigenetic activity of LSD2 as well as the interaction between LSD2 and other histone modifying enzymes in breast cancer cells.
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