Abstract 1044: Breast cancer subtype-specific regulation of gene transcription and therapeutic response by functional crosstalk between LSD1 and HDACs
Authors: Vasilatos Shauna , Katz Tiffany A. , Oesterreich Steffi , Davidson Nancy E. , Huang Yi 
Published: August 2012

The dysregulation of histone deacetylases (HDACs), which frequently leads to the silencing of gene expression, is linked to breast cancer progression. Studies in recent years have focused on reversing these changes in gene expression through inhibition of histone deacetylases (HDACs), and HDAC inhibitors (HDACi) have emerged as a potential new treatment option for cancer. However the current HDACi are less effective as monotherapy against solid tumors, highlighting the need to develop rational combinations of chemotherapeutic agents for the treatment of solid tumors. Our recent work has shown that combined inhibition of LSD1 and HDACs in breast cancer cell lines leads to re-expression of a unique subset of abnormally silenced genes and enhanced apoptosis in triple negative breast cancer (TNBC) cells, suggesting that crosstalk between lysine-specific demethylase 1 (LSD1) and HDACs is a novel and important epigenetic mechanism for aberrant gene silencing. These data also suggest that inhibition of LSD1 in combination with HDACi might enhance the therapeutic efficacy of HDAC inhibitors, and thus improve breast cancer treatment. Our further investigation showed that TNBC cells are overall more sensitive to combined treatment with LSD1 and HDAC inhibitors than other subtypes of breast tumors, or normal breast cells. LSD1-knockdown (KD) by shRNA sensitized TNBC MDA-MB-231 cells to HDACi-induced growth inhibition and apoptosis, and resulted in a striking synergistic mRNA induction of important growth control and apoptosis-related genes such as ERα, E-Cadherin, NR4A1, PCDH1, RGS16, BIK, CDKN1C, CRABP2, ING1, SQSTM1, TP53TG1, etc. In contrast, LSD1-KD exerted only minor effect on SAHA-induced gene re-expression in hormone receptor-positive or HER2 positive counterparts. Chromatin immunoprecipitation showed that re-expression of silenced genes was accompanied by concurrent increase of active chromatin marks H3K4me2 and AcetylH3K9 at gene promoters. ShRNA-mediated silencing of LSD1 significantly suppressed the mRNA expression of most of the class I (1-3, 8), II (6, 7, 10) and IV (11) HDAC isozymes in TNBC cells, but exerted marginal effect on transcription activities of HDAC isozymes in other subtypes of breast cancer cells. Moreover, siRNA-mediated silencing of the specific HDAC isozymes led to increase of H3K4me2 level in MDA-MB-231 cells. Taken together, our studies suggest that orchestrated interplay between LSD1 and HDACs is an important epigenetic signature contributing to aberrant gene silencing, and combination therapy targeting the crosstalk between histone demethylation and deacetylation may represent a novel therapeutic approach for aggressive TNBC.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1044. doi:1538-7445.AM2012-1044