Lactate Modulates Cellular Metabolism Through Histone Lactylation-Mediated Gene Expression in Non-Small Cell Lung Cancer

Abstract

Lactate has been observed to fuel TCA cycle and is associated with cancer progression in human lung cancer, the leading cause of cancer deaths worldwide, but the effect of lactate on lung cancer metabolism is rarely reported. In this study, disordered metabolism in non-small cell lung cancer was demonstrated by increased G6PD and SDHA protein levels via immunofluorescence, and up-regulated lactate dehydrogenase was found to be associated with poor prognosis. Then flow cytometry and Seahorse XFe analyzer were utilized to detect the effect of lactate on glycolysis and mitochondrial function in non-small cell lung cancer cells. The results show that in non-small cell lung cancer cells lactate attenuates glucose uptake and glycolysis while maintaining mitochondrial homeostasis as indicated by improved mitochondrial membrane potential. Further exploration found that mRNA levels of glycolytic enzymes (HK-1, PKM) and TCA cycle enzymes (SDHA, IDH3G) are respectively down-regulated and up-regulated by lactate, and increased histone lactylation was observed in promoters of HK-1 and IDH3G via chromatin immunoprecipitation assay. Taken together, the above results indicate that lactate modulates cellular metabolism at least in part through histone lactylation-mediated gene expression in non-small cell lung cancer.

Identification of lysine-lactylated substrates in gastric cancer cells

“…reported lactate-derived histone lysine lactylation (Kla) as a novel post-translational modification (PTM) that stimulated gene transcription in macrophages ( Zhang et al., 2019a ). The functions of histone Kla were then explored in mouse embryo fibroblasts (MEFs) ( Li et al., 2020a ), ocular melanoma cells ( Yu et al., 2021 ), and non-small cell lung cancer (NSCLC) cells ( Jiang et al., 2021 ); these studies indicated that Kla has important effects in regulating pluripotency and oncogenesis. Few studies have focused on Kla of non-histone proteins, although such studies have been conducted in Botrytis cinerea and Oryza sativa ( Gao et al., 2020 ; Meng et al., 2021 ).…”

Lactate receptor HCAR1 regulates cell growth, metastasis and maintenance of cancer‑specific energy metabolism in breast cancer cells

“…HCAR1 is highly expressed in breast cancer. To determine whether Hcar1 was expressed in cancer cells of solid tumours, whose interior are hypoxic and shows more lactate accumulation (20,21), Hcar1 mrna levels were analyzed in various cancer cell lines. it was found that Hcar1 was expressed in tongue, lung, breast, bladder, pancreatic, hepatocellular, colorectal, cervical and epidermal carcinoma cells (Fig.…”

Lactate-induced lactylation in skeletal muscle is associated with insulin resistance in humans

“…The goal of the current study was to determine if lactylation was present in human skeletal muscle utilizing a pan anti-Kla antibody commonly used to identify lactylation in other cell types ( Zhang et al, 2019 ; Chu et al, 2021 ; Cui et al, 2021 ; Hagiharai et al, 2021 ; Jiang et al, 2021 ; Meng et al, 2021 ). The confirmation of lactate-induced lactylation in human skeletal muscle advocates for future research to identify the specific proteins that undergo lactylation.…”