Immunology and Cancer Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Oncogene. 2018 May;37(22):2967-2981. doi: 10.1038/s41388-018-0172-9. Epub 2018 Mar 9.
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.
二甲双胍对 2 型糖尿病患者具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对抗癌症的确切分子机制尚未得到充分阐明。我们最近报道称，假激酶蛋白 TRIB3 作为一种应激传感器，通过抑制自噬和泛素-蛋白酶体降解系统来连接代谢应激与癌症促进；遗传上敲除 TRIB3 表达可减少肿瘤发生和癌症进展。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降低非糖尿病 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 的过表达可保护二甲双胍免受自噬流的激活、积累的肿瘤促进因子的清除以及肿瘤进展的减弱。我们进一步阐明了 TRIB3 作为衔接蛋白，招募赖氨酸乙酰转移酶 5（KAT5）到 SMAD3 上，并诱导 SMAD3 上依赖于磷酸化的 K333 乙酰化，维持 SMAD3 的转录活性，并随后增强 TRIB3 的转录。二甲双胍抑制 SMAD3 磷酸化并减少 KAT5/SMAD3 相互作用，从而减弱 KAT5 介导的 SMAD3 上的 K333 乙酰化，降低 SMAD3 的转录活性和随后的 TRIB3 表达，从而拮抗黑色素瘤的进展。总之，我们的研究不仅定义了二甲双胍通过扰乱糖尿病和非糖尿病小鼠中 KAT5/TRIB3/SMAD3 正反馈环来保护黑色素瘤进展的分子机制，而且还表明由于抑制应激蛋白 TRIB3 的表达，二甲双胍具有在肿瘤预防和治疗中的候选广泛用途。
