Hypoxia/lactate orchestrates the reprogramming metabolism of lung adenocarcinoma by modulating the SIRT2-mediated acetylation

BACKGROUND: Silent information regulator 2 (SIRT2) has been described to have dual roles as an oncogene and tumor suppressor gene in non-small cell lung cancer, but its functional selection and the precise mechanisms of its action remain to be elucidated. METHODS: lung adenocarcinoma (LUAD) tissue microarrays and cell lines were used to detect SIRT2 expression using Immunohistochemistry and Western blotting. SIRT2 overexpression, knockdown, and knockout LUAD cells were constructed to test SIRT2 function in vitro and in vivo, and targeted metabolomics, proteomics, and acetylation analyses were performed to explore the detailed mechanisms by which SIRT2 affects the biological characteristics of LUAD. RESULTS: SIRT2 is not only downregulated in LUAD tissues and cells, but also associated with poor prognosis in LUAD patients, not in lung squamous cell carcinoma. We also found that hypoxia-induced increasement in lactate levels led to this decreased SIRT2 expression. Remarkably, SIRT2 deficiency promotes the proliferation and metastasis of LUAD cells in vitro and in vivo, while SIRT2 overexpression exerts the opposite function. Mechanistically, SIRT2 deficiency leaded to increased acetylation levels of multiple enzymes involved in glycolysis, tricarboxylic acid cycle, fatty acid oxidation, and glutaminolysis. And results of co-inmunoprecipitation showed that SIRT2 bound to the above enzymes. Accordingly, SIRT2-deficient LUAD cells showed altered metabolic activities such as glycolysis, pentose phosphate pathway, TCA cycle, serine metabolism, and urea cycle. Notably, SIRT2 deletion increases glycolytic capacity of LUAD cells by increasing the acetylation modification of LDHA at the K118 site. CONCLUSION: This study reveals that hypoxia-induced lactate elevation decreases SIRT2 expression to promote LUAD progression, with the mechanism related to promoting glycolysis by increasing LDHA acetylation. In addition, decreased SIRT2 expression has also been found to cause alterations in many metabolic pathways with no verification mechanism.