Targeting Histone Abnormality in Triple-Negative Breast Cancer
Technical Report,01 Aug 2014,31 Jul 2018
University of Pittsburgh Pittsburgh United States
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During the entire funding period, our laboratory has closely collaborated with team of partnering PI to investigate the central hypothesis that abnormally enhanced crosstalk between LSD1 and HDAC is a unique epigenetic mechanism promoting triple negative breast cancer TNBC growth, and blockade of the HDAC-LSD1 axis results in profound inhibition of TNBC growth and metastasis. We have reported for the first time that LSD1 protein stability is promoted by HDAC5 through LSD1 associated ubiquitin-proteasome system, indicating that the regulation of LSD1 by HDAC5 is a posttranslational event. Our novel findings also demonstrated that an orchestrated interaction betweenHDAC5 and LSD1 is a critical epigenetic mechanism to suppress transcriptional activities of important tumor suppressor genes that may contribute to breast cancer development. We further revealed that HDAC5LSD1 axis is an effective drug target in breast cancer. Inhibition ofHDAC5LSD1 axis with a natural HDACi, sulforaphane, suppresses breast cancer growth in vitro and in vivo. Notably, combined treatment with a novel and potent LSD1 inhibitor, HCI-2509, improves the anticancer efficacy of sulforaphane in breast cancer cells. Our recent work suggested that inhibition of LSD1 significantly increased expression of T-cell chemokines and PD-L1 in TNBC cell lines. Combination of LSD1inhibitor and PD-1PD-L1 blockade exhibited significant synergy in hindering breast cancer progression. The interactive studies between two PIs have resulted in adequate accomplishments towards the proposed aims and publication of multiple original research papers in top-tier cancer research journals.
- Medicine and Medical Research