The Mechanism Of Metformin Suppresses Melanoma Progression

Metformin has significant effects on preventing and treating cancers among type 2 diabetic patients.Earlier studies have found that the incidence of malignant tumors in diabetic patients will increase significantly.This is one of particularly evidents in diabetics who have long-term insulin or insulinogues use.While using metformin to control blood glucose,the risk of a veriety of cancers was significantly decreased.Meanwhile,the prognosis of many cancer patients was significantly more favourable.Therefore,more and more studies have linked metformin treatment with reducing the risk of cancer in diabetics and improved prognosis in cancer patients.However,the role of metformin in non-diabetic cancer patients and the precise anti-cancer molecular mechanisms have not yet been sufficiently elucidated.Pseudo-protein kinase Tribble 3(TRIB3)is a member of Tribbles homologous protein family.TRIB3 highly expressed in a variety of tumor cell lines and human tumor tissues.It also plays an important regulatory role in tumorigenesis and tumor development by interacting with various signaling molecules.There are numerous reports that TRIB3 take effect as a stress sensor linking insulin and insulin-like growth factor to cancer promotion by inhibiting interaction with P62,autophagy and ubiquitin proteasomal degradation pathways.While knocking out TRIB3 at the gene level can significantly inhibit the occurrence and development of cancer.According to reports that TRIB3 mainly promotes tumorigenesis through its interaction with the transcription factor SMAD3.SMAD3 is located in the downstream of the TGF-?1 signaling pathway and involved in a variety of physiological and pathological processes as a key regulatory protein.In summary,TRIB3 can interact with a variety of signaling molecules,thereby promoting the occurrence and development of tumors.Thus,TRIB3 is a potential therapeutic target of cancer treatment.This article mainly explored the specific molecular mechanism of Metformin in decreasing the development of melanoma and found a new target,TRIB3,for metformin anti-tumor.And we also found a new TRIB3 acetylase-lysine acetyltransferase Tip60,KAT5.Whose aims are to provide experimental data for the clinical treatment of tumors with TRIB3 as a target,provide new strategies for the development of oncology drugs,and provide new ideas for the clinical treatments of tumors with metformin.Our study found that metformin inhibited the growth and metastasis of melanoma by suppressing the expression of TRIB3 in non-diabetic C57BL/6 mice and diabetic KK-Ay mice;Overexpression of TRIB3 reversed metformin-activated autophagic flow and cleared high expression promote tumorigenic factors and inhibit tumorgenesis and development.We further clarified that TRIB3 recruited lysine acetyltransferase Tip60(KAT5)to SMAD3 as a linker protein and mediates K333 acetylation of SMAD3 in a phosphorylation-dependent manner,thus maintaining the transcriptional activity of SMAD3 and the transcription level of TRIB3.Metformin suppresses SMAD3 phosphorylation and decreases KAT5/SMAD3 interaction,which attenuates the KAT5-mediated K333 acetylation of SMAD3,reduces SMAD3 transcriptional activity and subsequents TRIB3 expression,thus antagonizes melanoma progression.In summary,our study not only defines a molecular mechanism by which metformin protects against melanoma progression in diabetes and non-diabetes mice through interruption of the KAT5/TRIB3/SMAD3 positive feedback loop,but also suggests a candidate diverse utility of metformin in tumor prevention and therapy with suppressing expression of stress protein TRIB3.There is a certain potential target in the prevention and treatment of tumors.