SASH1 Inhibits Gastric Cancer Progression by Regulating YAP1-Mediated Metabolic Reprogramming.

Sterile alpha motif and SH3 domain-containing 1 (SASH1), a tumor suppressor, is involved in multiple biological processes in cancer cells. However, the potential role and mechanism of SASH1 in regulating glucose metabolism of gastric cancer (GC) remains unknown. SASH1 and Yes-associated protein 1 (YAP1) expressions in GC tissues were investigated based on The Cancer Genome Atlas (TCGA) database. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to analyze the expressions of the SASH1 and YAP1 in GC tissues and cell lines. Cell Counting kit-8 (CCK-8) and wound healing assays were conducted to measure the proliferation, migration and drug resistance. Commercial kits were used to assess the uptake of glucose and the productions of lactate and adenosine triphosphate (ATP). Extracellular acidification rate was measured using a microphysiometer. Co-Immunoprecipitation assay was performed to confirm the binding between SASH1 and YAP1. The results showed that SASH1 was decreased in GC tissues and cell lines. Overexpressing SASH1 inhibited the proliferation and migration, as well as decreased the drug resistance of GC cells. SASH1 decreased the uptake of glucose and extracellular acidification rate, as well as inhibited the productions of lactate and ATP. The expressions of glycolysis-related proteins were downregulated in GC cells with high SASH1 expression. Mechanistically, SASH1 regulated glucose metabolism reprogramming through promoting the phosphorylation and degradation of YAP1. Increased YAP1 reversed tumor-inhibiting effects of SASH1. In conclusion, SASH1 affected the phosphorylation and degradation of YAP1, thus suppressing the glycolysis and malignant biological behaviors of GC cells. The above findings revealed that SASH1 may be one of the molecular targets for GC therapy.