Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.
Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance.
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E3 连接酶 TRAF4 稳定 MCL-1 赋予放射抗性
DOI：
10.1038/s41419-022-05500-6
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发表时间：
2022-12-19
影响因子：
9
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Li, Ming;Gao, Feng;Li, Xiaoying;Gan, Yu;Han, Shuangze;Yu, Xinfang;Liu, Haidan;Li, Wei
E3连接酶肿瘤坏死因子受体相关因子4(TRAF4)在人类恶性肿瘤中经常过度表达，并与不良预后密切相关。然而，它对口腔鳞状细胞癌(OSCC)的致癌作用和放射敏感性的影响尚不清楚。目前的研究发现，TRAF4在原发和复发的口腔鳞癌组织中显著上调。去除TRAF4可显著提高口腔鳞癌细胞对放射治疗的敏感性，表明肿瘤细胞的增殖、集落形成和移植瘤生长均受到抑制。在机制上，IR促进TRAF4与Akt之间的相互作用，从而诱导Akt K63介导的泛素化和激活。TRAF4基因敲除可抑制Akt的磷酸化，上调GSK3的β活性，导致髓系白血病细胞白血病-1(MCL-1)S159的磷酸化增加，从而破坏MCL-1与约瑟芬结构域1(JOSD1)的相互作用，最终导致MCL-1泛素化和降解。此外，在原发和放疗后复发的肿瘤组织中，TRAF4与MCL-1呈正相关。一种MCL-1抑制剂克服了体内外的辐射抵抗。综上所述，本研究结果提示TRAF4通过Akt信号稳定MCL-1在口腔鳞癌中产生辐射抵抗，靶向TRAF4可能是克服口腔鳞癌放射抵抗的一种有前景的治疗策略。
The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of Akt and upregulated GSK3β activity, resulting in increased myeloid cell leukemia-1 (MCL-1) S159 phosphorylation, which disrupted the interaction of MCL-1 with Josephin domain containing 1 (JOSD1), and ultimately induced MCL-1 ubiquitination and degradation. Moreover, TRAF4 was positively correlated with MCL-1 in primary and in radiotherapy-treated, relapsed tumor tissues. An MCL-1 inhibitor overcame radioresistance in vitro and in vivo. Altogether, the present findings suggest that TRAF4 confers radioresistance in OSCC by stabilizing MCL-1 through Akt signaling, and that targeting TRAF4 may be a promising therapeutic strategy to overcome radioresistance in OSCC.
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