Dr. Huang’s research
interests focus on the investigation of epigenetic regulation of gene
expression in breast cancer. There is a growing body of evidence to suggest
that changes in the activity of chromatin-modifying enzymes contribute to the
uncontrolled cell proliferation and tumorigenesis. Importantly, epigenetic
changes, unlike mutations or loss of chromosomes, are reversible that provides
a rational mechanism for applying small molecule drugs as personalized
therapeutics to target these changes in cancer. Our main research objective is to
define in depth the mechanisms and biological consequences of functional
interplay between chromatin-modifying enzymes in breast cancer development. 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). LSD1 inhibitor in
combination with HDAC inhibitor displays superior synergy in blocking growth and
metastasis of TNBC cells. We are investigating the precise mechanisms
underlying orchestrated LSD1 and HDAC crosstalk in breast cancer and
determining how the dysregulated interaction of histone-modifying enzymes leads
to aberrant gene silencing and aggressive phenotype of TNBC. We are also studying
if targeting LSD1/HDAC crosstalk by novel inhibitors are more efficacious in hindering
TNBC growth than current strategies and thus represent a novel targeted therapy
for this devastating disease.
Another focus of the lab
is to determine the role of polyamine biosynthesis pathway in mediating the
activity of estrogen receptor signaling in breast cancer. Since the growth of
ER positive breast cancer largely relies on the action of estrogen,
antagonizing ER or its ligands is one of the most important strategies for
breast cancer treatment and prevention. Our recent study demonstrated that
inhibition of a key polyamine biosynthesis enzyme, ornithine decarboxylase
(ODC), diminishes ERa expression that leads to the loss of expression or function of
several important ERa target or partner genes including PR, NF-kB and cyclin D1. Loss of
ODC disrupts the binding of Sp1 and its newly identified co-factors (Pokemon,
PARP-1, myc, etc) to ERa minimal promoter element. Clinically, patients that initially respond to anti-estrogen
endocrine therapy will gradually develop resistance. This constitutes a major
clinical challenge in breast cancer therapy and prevention. Therefore,
development of more effective estrogen receptor modulators is necessary for
improving the therapeutic efficacy of breast cancer. We are investigating how
ODC mediates the expression and activity of ERa and elucidating
the potential role of ODC in endocrine resistance development in breast cancer.
Vasilatos SV, TA Katz, S Oesterreich,
Y Wan, NE Davidson and Y Huang.
Crosstalk between Lysine-specific Demethylase 1 (LSD1) and histone deacetylases
mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer
cells. Carcinogenesis 34:1196-207, 2013.
Huang Y, SN Vasilatos, L Boric, PG Shaw and NE Davidson. Inhibitors of histone demethylation and histone deacetylation cooperate in regulating gene expression and inhibiting growth in human breast cancer cells. Breast Cancer Research and Treatment 131:777-789, 2012.
Jin K, X Kong, T Shah, MF Pennet, F Wildes, DC Sgroi, XJ Ma, Y Huang, A Kallioniemi, G Landberg, I Bieche, X Wu, PE Lobie, NE Davidson, ZM Bhujwalla, T Zhu and S Sukumar. HOXB7 renders breast cancer resistant to tamoxifen through activation of the EGFR pathway. Proc Natl Acad Sci USA 109:2736-2741, 2012.
Zhu Q, L Jin, RA Casero, NE
Davidson and Y Huang. 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.
Hu D, Z Zhou, NE Davidson, Y Huang and Y Wan. Novel insight into
KLF4 proteolytic regulation in estrogen receptor signaling and breast carcinogenesis.
J Biol Chem 287:13584-13597, 2012.
Huang Y, S Nayak, R Jankowitz, NE
Davidson and S Oesterreich. Epigenetics in breast cancer-what’s new? Breast Cancer
Res 13:225, 2011.
Huang Y, TM Stewart, Y Wu, SB Baylin, LJ Marton, PM Woster and RA Casero. Novel oligoamine analogues inhibit lysine-specific demethylase 1 (LSD1) and induce re-expression of epigenetically silenced genes. Clin Cancer Res 15:7217-7228, 2009.
Huang Y, E Greene, TM Stewart, AC Goodwin, SB Baylin, PM Woster and RA Casero. Inhibition of the lysine specific demethylase, LSD1, by novel polyamine analogues results in re-expression of aberrantly silenced genes. Proc Natl Acad Sci USA 104:8023-8028, 2007.