TRIM67 Activates p53 to Suppress Colorectal Cancer Initiation and Progression
TRIM67 Activates p53 to Suppress Colorectal Cancer Initiation and Progression
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TRIM67 激活 p53 抑制结直肠癌的发生和进展
DOI：
10.1158/0008-5472.can-18-3614
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发表时间：
2019-08-15
期刊：
影响因子：
11.2
通讯作者：
Yu, Jun
中科院分区：
文献类型：
--
作者：
Wang, Shiyan;Zhang, Yanquan;Yu, Jun
三方基序(Triartite Motif，TRIM)家族蛋白参与多种重要的细胞过程，包括细胞凋亡、细胞周期停滞、DNA修复和衰老。在这项研究中，我们证明了一个新的TRIM家族成员，TRIM67，在结直肠癌中通常是沉默的，它的下调与较低的生存率有关。APC(Min/+)小鼠的Trim67基因敲除增加了结直肠癌的发生率、多样性和负担。同样，结肠特异的Trim67基因敲除显著加速了偶氮甲烷诱导的小鼠结直肠癌。RNA测序结果显示，TRIM67的抗肿瘤作用是通过激活P53信号通路实现的。TRIM67直接与P53的C末端相互作用，通过泛素连接酶MDM2抑制P53的降解。TRIM67也是P53的转录靶点；在细胞应激时，P53与TRIM67启动子结合并诱导TRIM67显著上调，从而形成TRIM67/P53自我放大环，促进P53诱导的细胞生长抑制和凋亡。因此，P53阳性调控程序的缺失严重影响了P53介导的对化疗诱导的DNA损伤的反应。在Trim67基因敲除小鼠的肿瘤和Trim67基因敲除的胚胎成纤维细胞中也观察到了抑制的P53反应。在体内外，TRIM67的重新激活恢复了P53的激活，并使结直肠癌细胞对化疗增敏。因此，TRIM67在结直肠癌中发挥着关键的肿瘤抑制作用，是提高化疗疗效的潜在靶点。意义：TRIM67/P53轴代表了一个新的治疗靶点，可以利用该靶点来提高野生型P53表达但P53信号受抑的结直肠癌的化疗疗效。
Tripartite motif (TRIM) family proteins participate in a variety of important cellular processes, including apoptosis, cell-cycle arrest, DNA repair, and senescence. In this study, we demonstrated that a novel TRIM family member, TRIM67, was commonly silenced in colorectal cancer and its downregulation was associated with poor survival. Trim67 knockout in Apc(Min/+) mice increased the incidence, multiplicity, and burden of colorectal tumors. Similarly, colon-specific knockout of Trim67 significantly accelerated azoxymethane-induced colorectal cancer in mice. RNA sequencing revealed that the anti-tumor effect of TRIM67 was mediated by activation of the p53 signaling pathway. TRIM67 interacted directly with the C-terminus of p53, inhibiting p53 degradation by its ubiquitin ligase MDM2. TRIM67 was also a transcriptional target of p53; upon cellular stress, p53 bound to the TRIM67 promoter and induced significant upregulation of TRIM67, thereby forming a TRIM67/p53 self-amplifying loop that boosts p53-induced cell growth inhibition and apoptosis. Consequently, loss of this p53-positive regulatory program profoundly compromised p53-mediated responses to chemotherapy-induced DNA damage. Dampened p53 response was also observed in tumors of Trim67 knockout mice and Trim67 knockout embryonic fibroblasts. TRIM67 reactivation restored p53 activation and sensitized colorectal cancer cells to chemotherapy in vitro and in vivo. TRIM67 thus functions as a pivotal tumor suppressor in colorectal cancer and is a potential target for improving chemotherapy responsiveness.Significance: The TRIM67/p53 axis represents a novel therapeutic target that could be harnessed to improve chemotherapy efficacy in colorectal cancer expressing wild-type p53 but with repressed p53 signaling.