Metformin promotes histone deacetylation of optineurin and suppresses tumour growth through autophagy inhibition in ocular melanoma

Abstract

Objective To explore the therapeutic potential and the underlying mechanism of metformin, an adenosine monophosphate‐activated kinase (AMPK) activator, in ocular melanoma. Methods CCK8, transwell, and colony formation assays were performed to detect the proliferation and migration ability of ocular melanoma cells. A mouse orthotopic xenograft model was built to detect ocular tumor growth in vivo. Western blot, immunofluorescence, and electron microscopy were adopted to evaluate the autophagy levels of ocular melanoma cells, and high‐throughput proteomics and CUT & Tag assays were performed to analyze the candidate for autophagy alteration. Results Here, we revealed for the first time that a relatively low dose of metformin induced significant tumorspecific inhibition of the proliferation and migration of ocular melanoma cells both in vitro and in vivo. Intriguingly, we found that metformin significantly attenuated autophagic influx in ocular melanoma cells. Through high‐throughput proteomics analysis, we revealed that optineurin (OPTN), which is a key candidate for autophagosome formation and maturation, was significantly downregulated after metformin treatment. Moreover, excessive OPTN expression was associated with an unfavorable prognosis of patients. Most importantly, we found that a histone deacetylase, SIRT1, was significantly upregulated after AMPK activation, resulting in histone deacetylation in the OPTN promoter. Conclusions Overall, we revealed for the first time that metformin significantly inhibited the progression of ocular melanoma, and verified that metformin acted as an autophagy inhibitor through histone deacetylation of OPTN. This study provides novel insights into metformin ‐ guided suppression of ocular melanoma and the potential mechanism underlying the dual role of metformin in autophagy regulation.

An injectable vitreous substitute with sustained release of metformin for enhanced uveal melanoma immunotherapy

“…27,28 However, the short elimination half-life of metformin has restricted its antitumor effects. [29][30][31] In our study, the injectable vitreous substitute with sustained metformin release ability (IVS-Met) prolonged the action of metformin and achieved an excellent long-term anti-tumor effect. Apart from direct tumor attack, IVS-Met could reduce the proportion of pro-tumor M2 phenotype tumor-associated macrophages (M2 TAMs) and induce pro-inflammatory M1 phenotype TAMs (M1 TAMs), therefore reversing the immunosuppressive TME and eliciting robust anti-tumor immune responses.…”

Construction and validation model of necroptosis-related gene signature associates with immunity for osteosarcoma patients

“…OPTN is short for Optineurin. Optineurin interacts with adenovirus E3-14.7 K protein and may reveal tumor necrosis factor-alpha or Fas-ligand pathways to mediate apoptosis, inflammation, or vasoconstriction 42 . TRIP6 stands for Thyroid Hormone Receptor Interactor 6.…”

Diabetes and skin cancers: Risk factors, molecular mechanisms and impact on prognosis

“…Notably, metformin suppressed miR-5100 expression while increasing SPINK5 expression, which inhibits STAT3 expression and Tyr705 phosphorylation[ 100 ]. Metformin significantly slows the progression of ocular melanoma through autophagy inhibition by histone deacetylation of optineurin[ 101 ]. Metformin increases the cytolytic activity of NK-92 cells over time and metformin-induced cytotoxicity was observed in NK cells from healthy peripheral blood and ascites of cancer patients.…”