GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer

Glutamate-ammonia ligase(GLUL, also known as glutamine synthetase) is a crucial enzyme that catalyzes ammonium and glutamate into glutamine in the ATP-dependent condensation. Although GLUL plays a critical role in multiple cancers, the expression and function of GLUL in gastric cancer remain unclear. In the present study, we have found that the expression level of GLUL was significantly lower in gastric cancer tissues compared with adjacent normal tissues, and correlated with N stage and TNM stage, and low GLUL expression predicted poor survival for gastric cancer patients. Knockdown of GLUL promoted the growth, migration, invasion and metastasis of gastric cancer cells in vitro and in vivo, and vice versa, which was independent of its enzyme activity. Mechanistically, GLUL competed with β-Catenin to bind to N-Cadherin, increased the stability of N-Cadherin and decreased the stability of β-Catenin by alerting their ubiquitination. Furthermore, there were lower N-Cadherin and higher β-Catenin expression levels in gastric cancer tissues compared with adjacent normal tissues. GLUL protein expression was correlated with that of N-Cadherin, and could be the independent prognostic factor in gastric cancer. Our findings reveal that GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progress of gastric cancer.

The potent roles of salt-inducible kinases(SIKs)in metabolic homeostasis and tumorigenesis

Salt-inducible kinases(SIKs)belong to AMP-activated protein kinase(AMPK)family,and functions mainly involve in regulating energy response-related physiological processes,such as gluconeogenesis and lipid metabolism.However,compared with another well-established energy-response kinase AMPK,SIK roles in human diseases,especially in diabetes and tumorigenesis,are rarely investigated.Recently,the pilot roles of SIKs in tumorigenesis have begun to attract more attention due to the finding that the tumor suppressor role of LKB1 in non-small-cell lung cancers(NSCLCs)is unexpectedly mediated by the SIK but not AMPK kinases.Thus,here we tend to comprehensively summarize the emerging upstream regulators,downstream substrates,mouse models,clinical relevance,and candidate inhibitors for SIKs,and shed light on SIKs as the potential therapeutic targets for cancer therapies.

AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma

Osteosarcoma(OS)is the most common primary malignant bone tumor in children and adolescents.Although activator of HSP90 ATPase activity 1(AHA1)is reported to be a potential oncogene,its role in osteosarcoma progression remains largely unclear.Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis,the relationship between AHA1 and cancer metabolism is unknown.In this study,we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients.AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo.Mechanistically,AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma.Notably,we identifed that isocitrate dehydrogenase 1(IDH1)is a novel client protein of Hsp90 AHA1.Furthermore,the IDH1 protein level was positively correlated with AHA1 in osteosarcoma.And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma.Moreover,high IDH1 level was also associated with poor prognosis of osteosarcoma patients.This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis,which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.