Serine hydroxymethyltransferase 2 knockdown induces apoptosis in ccRCC by causing lysosomal membrane permeabilization via metabolic reprogramming.

Serine hydroxymethyltransferase 2 (SHMT2) plays an important role in converting serine to glycine and supplying carbon to one-carbon metabolism to sustain cancer cell proliferation. However, the expression, function, and underlying mechanisms of SHMT2 in clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, we demonstrated that SHMT2 was upregulated in ccRCC tissues compared with controls and associated with patient survival. SHMT2 knockdown inhibited proliferation, migration, and invasion in ccRCC cells. Overexpression of SHMT2 promoted tumor progression. Mechanistically, SHMT2 depletion disrupted one-carbon metabolism, increased reactive oxygen species (ROS) levels, and decreased ATP levels via metabolic reprogramming, which destroyed cell homeostasis. The SHMT2 knockdown-induced stress activated autophagy. A mass of autophagosomes fused with lysosomes, resulting in lysosomal membrane permeabilization (LMP) and leakage of lysosomal contents into the cytoplasm, which eventually led to apoptosis. Our work reveals that SHMT2 functions as an oncogenic gene to promote ccRCC progression. SHMT2 depletion induces apoptosis by causing LMP through excessive activation of the autophagy-lysosome pathway via metabolic reprogramming.

Serine, glycine and one­carbon metabolism in cancer (Review).

Serine/glycine biosynthesis and one­carbon metabolism are crucial in sustaining cancer cell survival and rapid proliferation, and of high clinical relevance. Excessive activation of serine/glycine biosynthesis drives tumorigenesis and provides a single carbon unit for one­carbon metabolism. One­carbon metabolism, which is a complex cyclic metabolic network based on the chemical reaction of folate compounds, provides the necessary proteins, nucleic acids, lipids and other biological macromolecules to support tumor growth. Moreover, one­carbon metabolism also maintains the redox homeostasis of the tumor microenvironment and provides substrates for the methylation reaction. The present study reviews the role of key enzymes with tumor­promoting functions and important intermediates that are physiologically relevant to tumorigenesis in serine/glycine/one­carbon metabolism pathways. The related regulatory mechanisms of action of the key enzymes and important intermediates in tumors are also discussed. It is hoped that investigations into these pathways will provide new translational opportunities for human cancer drug development, dietary interventions, and biomarker identification.

Metabolomic-proteomic combination analysis reveals the targets and molecular pathways associated with hydrogen sulfide alleviating NAFLD.

AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide. Exogenous H2S has been shown to effectively mitigate NAFLD, although little is known about the underlying targets and molecular mechanisms. METHODS: C57BL/6 mice were fed with normal fat diet (NFD) or high fat diet (HFD) for a total 16 weeks, and HFD-fed mice were treated with saline or NaHS beginning in 12th week. The combination analysis of metabolomics and proteomics of liver tissues was firstly performed to discover the candidate targets and potential molecular pathways involved in H2S mitigating the NAFLD. KEY FINDINGS: Compared with NaCl, H2S relieved NAFLD by reducing liver weight, body weight and lipid accumulation in liver, and improving liver pathology and serum biochemical parameters. There were 40 overlapping metabolites in the intersection analysis between comparative analysis of HFD + NaCl vs NFD and HFD + NaHS vs HFD + NaCl based on liver metabolomics. Moreover, a total of 58 proteins were obtained whose changes were reversed after treatment with H2S. A combined analysis of liver metabolomics and proteomics was then conducted, revealing 8 shared molecular pathways, as well as the enrichment of unsaturated fatty acids. In addition, Plin2 may also be a potential target of H2S via the regulation of lipid droplet degradation in alleviating NAFLD. SIGNIFICANCE: We performed the first study combining metabolomics and proteomics to explore the mechanisms behind the alleviation of NAFLD by H2S. Our results not only provide evidence that H2S alleviates NAFLD but also reveals its possible molecular mechanisms and targets.