LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma.
LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma.
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DOI：
10.15252/emmm.202012525
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发表时间：
2020-11-06
影响因子：
11.1
通讯作者：
Obenauf AC
中科院分区：
文献类型：
--
作者：
Leiendecker L;Jung PS;Krecioch I;Neumann T;Schleiffer A;Mechtler K;Wiesner T;Obenauf AC
默克尔细胞癌（MCC）是一种高度侵袭性的神经内分泌皮肤癌，其缺乏可用于靶向治疗的可操作突变。表观遗传调节细胞身份可能代表未探索的治疗切入点。在这里，我们在药理学筛选中靶向表观遗传调节剂，发现赖氨酸特异性组蛋白脱甲基酶1A（LSD 1/KDM 1A）是MCC体外和体内生长所必需的。我们发现，MCC中的LSD 1抑制破坏了LSD 1-CoREST复合物，导致HMG 20 B（BRAF 35）的置换和降解，这是一种对MCC增殖至关重要的表征不佳的复合物成员。LSD 1的抑制引起神经元谱系的转录主调节因子的去抑制，激活类似于正常默克尔细胞的基因表达特征，并诱导细胞周期停滞和细胞死亡。我们的研究揭示了LSD 1在MCC中维持细胞可塑性和增殖的重要性。越来越多的证据表明，癌细胞利用细胞可塑性和去分化程序来逃避免疫系统的破坏。因此，LSD 1抑制剂与检查点抑制剂的组合可能代表MCC患者的有希望的治疗策略。本研究确定了LSD 1-CoREST复合物的完整性对于默克尔细胞癌（MCC）增殖和维持细胞身份至关重要。LSD 1抑制导致神经元谱系的转录调节因子的去抑制，并且是MCC中靶向治疗的新切入点。
Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine‐specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1‐CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients. This study identifies that the integrity of the LSD1‐CoREST complex is essential for Merkel cell carcinoma (MCC) proliferation and maintaining cell identity. LSD1 inhibition causes derepression of transcriptional regulators of the neuronal lineage and is a novel entry point for targeted therapies in MCC.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Ballas, N;Grunseich, C;Mandel, G
通讯作者：
Mandel, G
影响因子：
--
作者：
Crowley, Lisa C;Christensen, Melinda E;Waterhouse, Nigel J
通讯作者：
Waterhouse, Nigel J
DOI：
10.1073/pnas.96.17.9873
发表时间：
1999-08-17
影响因子：
11.1
作者：
Andrés, ME;Burger, C;Mandel, G
通讯作者：
Mandel, G
影响因子：
8.8
作者：
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通讯作者：
Capell, Brian C.