Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression
Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression
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二甲双胍通过抑制 KAT5 介导的 SMAD3 乙酰化、转录活性和 TRIB3 表达来抑制黑色素瘤进展
DOI：
10.1038/s41388-018-0172-9
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发表时间：
2018-05-01
期刊：
影响因子：
8
通讯作者：
Hu, Zhuo-wei
中科院分区：
文献类型：
--
作者：
Li, Ke;zhang, Ting-ting;Hu, Zhuo-wei
二甲双胍对2型糖尿病患者有预防和治疗癌症的有益作用。然而，二甲双胍在非糖尿病癌症患者中的作用以及抗癌的确切分子机制尚未被充分阐明。我们最近报道，伪激酶蛋白TRIB3作为压力传感器，通过抑制自噬和泛素-蛋白酶体降解系统，将代谢应激源与癌症促进联系起来；从基因上消除TRIB3的表达可以减少肿瘤的发生和癌症的进展。因此，TRIB3是多种癌症的潜在治疗靶点。在这项研究中，我们发现二甲双胍通过减少非糖尿病C57BL/6小鼠和糖尿病KK-Ay小鼠中TRIB3的表达来抑制黑色素瘤的生长和转移；TRIB3的过表达保护二甲双胍免受自噬通量的激活、累积的促肿瘤因子的清除和肿瘤进展的抑制。我们进一步阐明了TRIB3作为一个接头，将赖氨酸乙酰转移酶5(KAT5)募集到Smad3上，并诱导Smad3的K333乙酰化，从而维持Smad3的转录活性，进而增强TRIB3的转录。二甲双胍抑制Smad3的磷酸化，减少KAT5/Smad3的相互作用，从而减弱KAT5介导的Smad3的K333乙酰化，降低Smad3的转录活性和随后的TRIB3表达，从而抑制黑色素瘤的发展。综上所述，我们的研究不仅确定了二甲双胍通过干扰糖尿病和非糖尿病小鼠的KAT5/TRIB3/Smad3正反馈循环来防止黑色素瘤进展的分子机制，而且由于抑制了应激蛋白TRIB3的表达，也表明了二甲双胍在肿瘤预防和治疗中的潜在不同用途。
Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression. Thus, TRIB3 is a potential therapeutic target for diverse cancers. In this study, we found that metformin attenuates melanoma growth and metastasis by reducing TRIB3 expression in non-diabetic C57BL/6 mice and diabetic KK-Ay mice; overexpression of TRIB3 protects metformin from the activation of autophagic flux, the clearance of accumulated tumour-promoting factors and the attenuation of tumour progression. We further elucidated that TRIB3 acts as an adaptor to recruit lysine acetyltransferase 5 (KAT5) to SMAD3 and induce a phosphorylation-dependent K333 acetylation of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation and decreases the KAT5/SMAD3 interaction, to attenuate the KAT5-mediated K333 acetylation of SMAD3, reduce the SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby antagonizes melanoma progression. Together, our study not only defines a molecular mechanism by which metformin protects against melanoma progression by disturbing the KAT5/TRIB3/SMAD3 positive feedback loop in diabetes and non-diabetes mice, but also suggests a candidate diverse utility of metformin in tumour prevention and therapy because of suppressing stress protein TRIB3 expression.