E3 连接酶 TRAF4 稳定 MCL-1 赋予放射抗性,Cell Death & Disease

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E3 连接酶 TRAF4 稳定 MCL-1 赋予放射抗性
Cell Death & Disease ( IF 8.1 ) Pub Date : 2022-12-19 , DOI: 10.1038/s41419-022-05500-6
Ming Li _{1,

2,

3,

4} , Feng Gao _{1,

5} , Xiaoying Li ₄ , Yu Gan ₄ , Shuangze Han _{4,

6} , Xinfang Yu _{1,

7} , Haidan Liu _{8,

9} , Wei Li _{1,

4}

Affiliation

Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, People's Republic of China.
Changsha Stomatological Hospital, Changsha, Hunan, 410004, People's Republic of China.
School of Stomatology, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People's Republic of China.
Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, People's Republic of China.
Department of Ultrasonography, The Third Xiangya Hospital of Central South University, Changsha, Hunan, 410013, People's Republic of China.
Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, People's Republic of China.
Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.
Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People's Republic of China.

E3 连接酶 TNF 受体相关因子 4 (TRAF4) 经常过度表达，并且与人类恶性肿瘤的不良预后密切相关。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仍不清楚。本研究发现 TRAF4 在原发性和复发性 OSCC 肿瘤组织中显着上调。TRAF4 的消耗显着提高了 OSCC 细胞对辐射 (IR) 治疗的敏感性，表明肿瘤细胞增殖、集落形成和异种移植肿瘤生长减少。从机制上讲，IR 促进 TRAF4 和 Akt 之间的相互作用，从而诱导 Akt K63 介导的泛素化和激活。TRAF4 敲除抑制 Akt 磷酸化并上调 GSK3β 活性，导致髓样细胞白血病-1 (MCL-1) S159 磷酸化增加，它破坏了 MCL-1 与包含 1 (JOSD1) 的约瑟芬结构域的相互作用，并最终诱导了 MCL-1 泛素化和降解。此外，TRAF4 与 MCL-1 在原发性和放射治疗后的复发肿瘤组织中呈正相关。MCL-1 抑制剂克服了体外和体内的放射抗性。总而言之，目前的研究结果表明，TRAF4 通过 Akt 信号稳定 MCL-1 来赋予 OSCC 放射抗性，靶向 TRAF4 可能是克服 OSCC 放射抗性的有前途的治疗策略。MCL-1 抑制剂克服了体外和体内的放射抗性。总而言之，目前的研究结果表明，TRAF4 通过 Akt 信号稳定 MCL-1 来赋予 OSCC 放射抗性，靶向 TRAF4 可能是克服 OSCC 放射抗性的有前途的治疗策略。MCL-1 抑制剂克服了体外和体内的放射抗性。总而言之，目前的研究结果表明，TRAF4 通过 Akt 信号稳定 MCL-1 来赋予 OSCC 放射抗性，靶向 TRAF4 可能是克服 OSCC 放射抗性的有前途的治疗策略。

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Stabilization of MCL-1 by E3 ligase TRAF4 confers radioresistance

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.

更新日期：2022-12-19

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