Histone methyltransferase SETD2 regulates TKT expression and mediates glycolysis to suppress lung adenocarcinoma progression and improve chemosensitivity

Histone methyltransferase SETD2 is frequently downregulated in various malignancies and plays a critical role in regulating tumor progression. However, its biological role in lung adenocarcinoma (LUAD), especially its regulation of glycolysis and chemosensitivity, has not been fully elucidated. Transketolase (TKT) is a crucial enzyme in glycolysis, but whether it is involved in the regulation of LUAD progression and chemosensitivity by SETD2 remains unclear. Cisplatin (CIS)-resistant cells were established, and SETD2 and TKT expression levels were assessed via Western blot. The malignant phenotype of LUAD cells was evaluated through CCK-8 assay, scratch healing, colony formation, and Transwell assay; while apoptosis was determined by flow cytometry. The binding relationship between SETD2 and TKT was verified by ChIP and dual luciferase reporter gene assays. Glycolytic activity was measured using commercial kits. A LUAD tumor model was established in nude mice, and apoptosis and proliferation were detected by TUNEL staining and Ki-67 immunohistochemistry, respectively. SETD2 expression was diminished in LUAD tissues and CIS-resistant cell lines. Overexpression of SETD2 attenuated the malignant phenotype of LUAD cells, promoted apoptosis, and increased the chemosensitivity of CIS-resistant cells. Meanwhile, SETD2 overexpression reduced the glycolytic activity in LUAD cells, as evidenced by decreased glucose uptake, ATP and lactate production, and downregulation of key proteins in the glycolytic pathway. Mechanistically, SETD2 bound to the TKT promoter and suppressed its transcription. Furthermore, TKT overexpression partially reversed the regulatory impacts of SETD2 on LUAD cells. Additionally, SETD2 overexpression suppressed tumor growth by down-regulating TKT, reduced glycolysis level in tumor tissues, promoted apoptosis and inhibited proliferation of tumor cells. In conclusion, SETD2 inhibits glycolysis by directly suppressing TKT transcription, thereby attenuating malignant progression and enhancing chemosensitivity in LUAD.