Figures & data
Figure 1. Metformin suppresses melanoma progression by reducing SMAD3-mediated TRIB3 expression and restoring autophagy flux. TRIB3 hinders the binding of SQSTM1 to LC3 and ubiquitinated proteins, leading to SQSTM1 accumulation and inhibition of the clearance of ubiquitinated proteins, which promotes tumor growth and metastasis by inhibiting autophagic flux and the ubiquitin-proteasome system (UPS). Metformin attenuates melanoma by reducing TRIB3 expression and activating autophagy; TRIB3 overexpression protects metformin from the activation of autophagic flux and the attenuation of tumor progression. Mechanistically, TRIB3 acts as an adaptor to recruit KAT5 (lysine acetyltransferase 5) to SMAD3 and induce a phosphorylation (P)-dependent K333 acetylation (A) of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation through the following: 1) metformin interacts with the receptor-binding domain of TGFB1 and reduces its binding probability with TGFBR1/TβRI but not TGFBR2/TβRII; 2) metformin suppresses the interaction of TGFBR1 and SMAD3 caused by TGFB1 stimulation. Reduced SMAD3 phosphorylation impedes the KAT5-SMAD3 interaction and protects against the KAT5-mediated K333 acetylation of SMAD3, which reduces SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby restoring autophagy and antagonizing melanoma progression.
