2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
J Mol Cell Biol. 2018 Aug 1;10(4):285-301. doi: 10.1093/jmcb/mjy021.
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.
赖氨酸特异性脱甲基酶 1（LSD1）是第一个被鉴定为催化组蛋白 H3-K4 单甲基化和二甲基化标记去除的组蛋白去甲基酶。尽管 LSD1 在转录调控中可能具有广泛的作用，但最近的研究表明，LSD1 可能与包括 CoREST/HDAC 复合物、NuRD 复合物、SIRT1 和 PRC2 在内的多个表观遗传调控复合物协同作用，这意味着这种看似简单的酶具有复杂的作用机制。在这里，我们报告 LSD1 也是 SIN3A/HDAC 复合物的一个组成部分。使用 ChIP-on-chip 技术进行转录靶标分析表明，LSD1/SIN3A/HDAC 复合物靶向几个细胞信号通路，这些信号通路对于细胞增殖、存活、转移和凋亡至关重要，特别是 p53 信号通路。我们已经证明，LSD1 与 SIN3A/HDAC 复合物协同作用，抑制一系列基因，如 CASP7、TGFB2、CDKN1A(p21)、HIF1A、TERT 和 MDM2，其中一些基因是致癌基因。我们的实验还发现，LSD1 和 SIN3A 对于乳腺癌细胞的最佳存活和生长是必需的，同时对于维持上皮细胞的稳态和化疗敏感性也是必需的。我们的数据表明，LSD1 是 SIN3A/HDAC 复合物的功能性替代亚基，为组蛋白去甲基化和去乙酰化在染色质重塑中的相互作用提供了分子基础，并表明 LSD1/SIN3A/HDAC 复合物可能成为乳腺癌治疗策略的靶点。
