Oncogenic Actions of the Nuclear Receptor Corepressor (NCOR1) in a Mouse Model of Thyroid Cancer
Oncogenic Actions of the Nuclear Receptor Corepressor (NCOR1) in a Mouse Model of Thyroid Cancer
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DOI：
10.1371/journal.pone.0067954
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发表时间：
2013-06-26
期刊：
影响因子：
3.7
通讯作者：
Cheng, Sheue-yann
中科院分区：
文献类型：
--
作者：
Fozzatti, Laura;Park, Jeong Won;Cheng, Sheue-yann
研究表明核受体辅阻遏物 1 (NCOR1) 可能在人类癌症中发挥重要作用。然而，其在体内发挥作用影响癌症进展的详细分子机制尚不清楚。本研究利用自发发展为甲状腺癌的小鼠模型（Thrb（PV/PV）小鼠）阐明了 NCOR1 在致癌作用中的体内作用。 Thrb(PV/PV) 小鼠具有显性阴性甲状腺激素受体β (TR beta) 突变体（表示为PV）。我们采用了功能丧失的方法，将 Thrb(PV) 小鼠与全局表达 NCOR1 突变蛋白 (NCOR1 Delta ID) 的小鼠杂交，其中受体相互作用域已被修改，使其无法与小鼠中的 TR beta 或 PV 相互作用。值得注意的是，NCOR1 Delta ID 蛋白的表达减少了甲状腺肿瘤的生长，显着延迟了肿瘤进展，并延长了 Thrb(PV/PV) Ncor1(Delta ID/Delta ID) 小鼠的生存期。细胞周期蛋白依赖性激酶抑制剂 1 (p21(waf1/cip1)；Cdkn1A) 表达增加可抑制肿瘤细胞增殖，促凋亡 BCL 相关 X (Bax) 表达增加可激活细胞凋亡。进一步的分析表明，p53 被招募到 Cdkn1A 和 Bax 基因近端启动子上的 p53 结合位点，作为与 PV/NCOR1/组蛋白脱乙酰基酶 3 (HDAC-3) 的共抑制复合物，导致 Thrb(PV/PV) 小鼠甲状腺中 Cdkn1A 和 Bax 基因的抑制。在 Thrb(PV/PV) Ncor1(Delta ID/Delta ID) 小鼠的甲状腺中，p53/PV 复合物无法募集 NCOR1 Delta ID 和 HDAC-3，从而导致这两个基因的去抑制，从而抑制癌症进展。目前的研究提供了体内直接证据，表明 NCOR1 可以在甲状腺癌小鼠模型中通过转录调节发挥癌基因的作用。
Studies have suggested that the nuclear receptor corepressor 1 (NCOR1) could play an important role in human cancers. However, the detailed molecular mechanisms by which it functions in vivo to affect cancer progression are not clear. The present study elucidated the in vivo actions of NCOR1 in carcinogenesis using a mouse model (Thrb(PV/PV) mice) that spontaneously develops thyroid cancer. Thrb(PV/PV) mice harbor a dominantly negative thyroid hormone receptor beta (TR beta) mutant (denoted as PV). We adopted the loss-of-the function approach by crossing Thrb(PV) mice with mice that globally express an NCOR1 mutant protein (NCOR1 Delta ID) in which the receptor interaction domains have been modified so that it cannot interact with the TR beta, or PV, in mice. Remarkably, expression of NCOR1 Delta ID protein reduced thyroid tumor growth, markedly delayed tumor progression, and prolonged survival of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice. Tumor cell proliferation was inhibited by increased expression of cyclin-dependent kinase inhibitor 1 (p21(waf1/cip1); Cdkn1A), and apoptosis was activated by elevated expression of pro-apoptotic BCL-Associated X (Bax). Further analyses showed that p53 was recruited to the p53-binding site on the proximal promoter of the Cdkn1A and the Bax gene as a co-repressor complex with PV/NCOR1/histone deacetylas-3 (HDAC-3), leading to repression of the Cdkn1A as well as the Bax gene in thyroids of Thrb(PV/PV) mice. In thyroids of Thrb(PV/PV) Ncor1(Delta ID/Delta ID) mice, the p53/PV complex could not recruit NCOR1 Delta ID and HDAC-3, leading to de-repression of both genes to inhibit cancer progression. The present studies provided direct evidence in vivo that NCOR1 could function as an oncogene via transcription regulation in a mouse model of thyroid cancer.