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Targeting Histone Abnormality in Triple Negative Breast Cancer

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Technical Report,01 Aug 2014,31 Jul 2015

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University of Pittsburgh Pittsburgh United States

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In the first funding year, we tested our hypothesis that silencing of key tumor suppressive genes by enhanced crosstalk between LSD1 and HDACs is a unique epigenetic mechanism promoting TNBC growth, and blockade of the LSD1HDAC axis results in profound inhibition of TNBC growth and metastasis, mediated at least in part via induction of RGS16. We demonstrated that HDAC5 physically interacted with LSD1 complex through NLS domain, and promoted LSD1 protein stability through upregulating LSD1-specific deubiquitinase USP28. Increased cellular proliferation mediated by HDAC5 overexpression was diminished by LSD1-KD, suggesting a critical role of LSD1 in regulating oncogenic activity of HDAC5. By using MCF10A TNBC tumor progression model, we observed that HDAC5-LSD1 axis possesses a critical oncogenic function in driving breast cancer development. Moreover, teams of the two PIs collaborated to study the combinatorial effect of natural HDAC inhibitor sulphoraphane and novel LSD1 inhibitor HCI-2509 on growth of MDA-MB-231 cells using xenograft model. These new findings provide solid evidence to suggest that crosstalk between LSD1 and HDACs represents a rational target for the development of drugs that can block their activity in TNBC cells.

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