Merkel Cell Carcinoma Sensitivity to EZH2 Inhibition Is Mediated by SIX1 Derepression.
Merkel Cell Carcinoma Sensitivity to EZH2 Inhibition Is Mediated by SIX1 Derepression.
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DOI：
10.1016/j.jid.2022.03.008
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发表时间：
2022-10
影响因子：
6.5
通讯作者：
DeCaprio, James A.
中科院分区：
文献类型：
--
作者：
Gartin, Ashley K.;Frost, Thomas C.;Cushman, Camille H.;Leeper, Brittaney A.;Gokhale, Prafulla C.;DeCaprio, James A.
多梳抑制复合物2（PRC 2）在维持二价启动子中具有关键作用，并且经常在癌症（包括神经内分泌肿瘤）中受到干扰。在这里，我们调查的敏感性默克尔细胞癌（MCC），神经内分泌癌的皮肤，抑制剂的PRC 2催化亚基EZH 2。我们表明，MCC细胞系的一个子集是敏感的EZH 2肿瘤诱导的细胞活力丧失。我们发现，敏感细胞的抑制剂治疗解除了PRC 2靶点SIX 1的抑制，SIX 1是PAX-SIX-EYA-DACH网络（PSEDN）中通常参与内耳毛细胞发育的转录因子，PSEDN转录因子是EZH 2受体诱导的MCC细胞活力丧失的关键因素。此外，我们表明EZH 2抑制剂tazemetostat减缓了MCC异种移植物的生长，并在体内解除了SIX 1及其下游内耳靶基因MYO 6的抑制。我们认为MCC中的EZH 2抑制导致SIX 1去抑制，伴随听力相关转录程序的失调和生长抑制。这项研究提供的证据表明，MCC肿瘤可能对EZH 2抑制剂特别敏感，同时对这些抑制剂在MCC中干扰的转录程序以及其他神经内分泌癌症中的潜在机制进行了深入研究。
Polycomb repressive complex 2 (PRC2) has a critical role in the maintenance of bivalent promoters and is often perturbed in cancer, including neuroendocrine tumors. Here we investigate the susceptibility of Merkel cell carcinoma (MCC), a neuroendocrine carcinoma of the skin, to inhibitors of the PRC2 catalytic subunit EZH2. We show that a subset of MCC cell lines is sensitive to EZH2 inhibitor-induced cell viability loss. We find that inhibitor treatment of susceptible cells derepresses the PRC2 target SIX1, a transcription factor in the PAX-SIX-EYA-DACH network (PSEDN) normally involved in inner ear hair cell development, and that PSEDN transcription factors are critical contributors to EZH2 inhibitor-induced MCC cell viability loss. Furthermore, we show the EZH2 inhibitor tazemetostat slows the growth of MCC xenografts and derepresses SIX1 and its downstream inner ear target gene MYO6 in vivo. We propose that EZH2 inhibition in MCC leads to SIX1 derepression, with dysregulation of hearing-related transcriptional programs and growth inhibition. This study provides evidence that MCC tumors may be specifically susceptible to EZH2 inhibitors while giving mechanistic insight into the transcriptional programs these inhibitors perturb in MCC, and potentially in other neuroendocrine cancers.
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影响因子：
11.1
作者：
Leiendecker L;Jung PS;Krecioch I;Neumann T;Schleiffer A;Mechtler K;Wiesner T;Obenauf AC
通讯作者：
Obenauf AC
影响因子：
10.5
作者：
Cohen I;Bar C;Liu H;Valdes VJ;Zhao D;Galbo PM Jr;Silva JM;Koseki H;Zheng D;Ezhkova E
通讯作者：
Ezhkova E
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
DOI：
10.1073/pnas.1703966114
发表时间：
2017-11-14
影响因子：
11.1
作者：
Januario, Thomas;Ye, Xiaofen;Yauch, Robert L.
通讯作者：
Yauch, Robert L.
影响因子：
9.8
作者：
Azaiez H;Booth KT;Ephraim SS;Crone B;Black-Ziegelbein EA;Marini RJ;Shearer AE;Sloan-Heggen CM;Kolbe D;Casavant T;Schnieders MJ;Nishimura C;Braun T;Smith RJH
通讯作者：
Smith RJH