LSD1 coordinates with the SIN3A/HDAC complex and maintains sensitivity to chemotherapy in breast cancer

Abstract

Lysine-specific demethylase 1 (LSD1) was the first histone demethylase identified as catalysing the removal of mono- and di-methylation marks on histone H3-K4. Despite the potential broad action of LSD1 in transcription regulation, recent studies indicate that LSD1 may coordinate with multiple epigenetic regulatory complexes including CoREST/HDAC complex, NuRD complex, SIRT1, and PRC2, implying complicated mechanistic actions of this seemingly simple enzyme. Here, we report that LSD1 is also an integral component of the SIN3A/HDAC complex. Transcriptional target analysis using ChIP-on-chip technology revealed that the LSD1/SIN3A/HDAC complex targets several cellular signalling pathways that are critically involved in cell proliferation, survival, metastasis, and apoptosis, especially the p53 signalling pathway. We have demonstrated that LSD1 coordinates with the SIN3A/HDAC complex in inhibiting a series of genes such as CASP7, TGFB2, CDKN1A(p21), HIF1A, TERT, and MDM2, some of which are oncogenic. Our experiments also found that LSD1 and SIN3A are required for optimal survival and growth of breast cancer cells while also essential for the maintenance of epithelial homoeostasis and chemosensitivity. Our data indicate that LSD1 is a functional alternative subunit of the SIN3A/HDAC complex, providing a molecular basis for the interplay of histone demethylation and deacetylation in chromatin remodelling, and suggest that the LSD1/SIN3A/HDAC complex could be a target for breast cancer therapeutic strategies.