Crosstalk between lysine-specific demethylase 1 (LSD1) and histone deacetylases mediates antineoplastic efficacy of HDAC inhibitors in human breast cancer cells

Abstract

Our previous studies demonstrated that lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) closely interact in controlling growth of breast cancer cells. However, the underlying mechanisms are largely unknown. In this study, we showed that knockdown of LSD1 expression (LSD1-KD) by RNAi decreased mRNA levels of HDAC isozymes in triple-negative breast cancer (TNBC) cells. Small interfering RNA (siRNA)-mediated depletion of HDAC5 expression induced the most significant accumulation of H3K4me2, a specific substrate of LSD1. Combined treatment with LSD1 inhibitor, pargyline, and HDAC inhibitor, SAHA (Vorinostat), led to superior growth inhibition and apoptotic death in TNBC cells, but exhibited additive or antagonistic effect on growth inhibition in non-TNBC counterparts or non-tumorigenic breast cells. Additionally, LSD1-KD enhanced SAHA-induced reexpression of a subset of aberrantly silenced genes, such as NR4A1, PCDH1, RGS16, BIK, and E-cadherin whose reexpression may be tumor suppressive. Genome-wide microarray study in MDA-MB-231 cells identified a group of tumor suppressor genes whose expression was induced by SAHA and significantly enhanced by LSD1-KD. We also showed that concurrent depletion of RGS16 by siRNA reduced overall cytotoxicity of SAHA and blocked the reexpression of E-cadherin, CDKN1C and ING1 in LSD1-deficient MDA-MB-231 cells. Furthermore, cotreatment with RGS16 siRNA reversed the downregulation of nuclear factor-kappaB expression induced by combined inhibition of LSD1 and HDACs, suggesting a crucial role of RGS16 in controlling key pathways of cell death in response to combination therapy. Taken together, these results provide novel mechanistic insight into the breast cancer subtype-dependent role of LSD1 in mediating HDAC activity and therapeutic efficacy of HDAC inhibitor.

Histone Lysine-specific Demethylase 1 (LSD1) Protein Is Involved in Sal-like Protein 4 (SALL4)-mediated Transcriptional Repression in Hematopoietic Stem Cells

“…Here, it may be critical to consider that histone modification and DNA methylation cooperatively regulate chromatin structure and gene activity. For example, loss of LSD1 mediated by shRNA is found to suppress HDAC mRNA expressions in breast cancer cells (33). We have also verified the reduced mRNA levels of HDAC1 and HDAC2 after LSD1 knockdown in BM HSPCs.…”

Functional interaction of histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) promotes breast cancer progression

“…A role for elevated expression of LSD1 has been implicated in tumorigenesis in various cancers including breast cancer (3, 5–9). Studies from our and other laboratories consistently showed that inhibition of LSD1 hindered proliferation of breast cancer cells (6, 8, 10). Lim et al reported that LSD1 is highly expressed in ER-negative breast cancers (6).…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…Preclinical studies also indicate a synergistic antitumor effect of HDACi with other epigenetic-targeted drugs, such as lysine-specific histone demethylase inhibitors (Vasilatos et al 2013; Fiskus et al 2014). These observations are consistent with recent findings that broad-acting HDAC inhibitors have minimal effect on promoter acetylation, but rather they promote H3K27 trimethylation, a silencing-associated histone modification (Halsall et al 2015).…”