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Msn2/4 regulate expression of glycolytic enzymes and control transition from quiescence to growth.

ABSTRACT: Nutrient availability and stresses impact a cell's decision to enter a growth state or a quiescent state. Acetyl-CoA stimulates cell growth under nutrient-limiting conditions, but how cells generate acetyl-CoA under starvation stress is less understood. Here, we show that general stress response factors, Msn2 and Msn4, function as master transcriptional regulators of yeast glycolysis via directly binding and activating genes encoding glycolytic enzymes. Yeast cells lacking Msn2 and Msn4 exhibit prevalent repression of glycolytic genes and a significant delay of acetyl-CoA accumulation and reentry into growth from quiescence. Thus Msn2/4 exhibit a dual role in activating carbohydrate metabolism genes and stress response genes. These results suggest a possible mechanism by which starvation-induced stress response factors may prime quiescent cells to reenter growth through glycolysis when nutrients are limited.

SUBMITTER: Kuang Z

PROVIDER: S-EPMC5634782 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Msn2/4 regulate expression of glycolytic enzymes and control transition from quiescence to growth.

Kuang Zheng Z Pinglay Sudarshan S Ji Hongkai H Boeke Jef D JD

eLife 20170926

Nutrient availability and stresses impact a cell's decision to enter a growth state or a quiescent state. Acetyl-CoA stimulates cell growth under nutrient-limiting conditions, but how cells generate acetyl-CoA under starvation stress is less understood. Here, we show that general stress response factors, Msn2 and Msn4, function as master transcriptional regulators of yeast glycolysis via directly binding and activating genes encoding glycolytic enzymes. Yeast cells lacking Msn2 and Msn4 exhibit ...[more]

PMID: 28949295

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Project description:BackgroundNovel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors.MethodsExpression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought. The effect of glycolysis pathway inhibitors on the growth of a panel of ovarian cancer cell lines was assessed by use of the SRB proliferation assay. Combination studies were undertaken combining these inhibitors with cytotoxic agents.ResultsMean expression levels of GLUT1 and HKII were higher in high grade serous ovarian cancer (HGSOC), the most frequently occurring subtype, than in non-HGSOC. GLUT1 expression was also significantly higher in advanced stage (III/IV) ovarian cancer than early stage (I/II) disease. Growth dependency of ovarian cancer cells on glucose was demonstrated in a panel of ovarian cancer cell lines. Inhibitors of the glycolytic pathway (STF31, IOM-1190, 3PO and oxamic acid) attenuated cell proliferation in platinum-sensitive and platinum-resistant HGSOC cell line models in a concentration dependent manner. In combination with either cisplatin or paclitaxel, 3PO (a novel PFKFB3 inhibitor) enhanced the cytotoxic effect in both platinum sensitive and platinum resistant ovarian cancer cells. Furthermore, synergy was identified between STF31 (a novel GLUT1 inhibitor) or oxamic acid (an LDH inhibitor) when combined with metformin, an inhibitor of oxidative phosphorylation, resulting in marked inhibition of ovarian cancer cell growth.ConclusionsThe findings of this study provide further support for targeting the glycolytic pathway in ovarian cancer and several useful combinations were identified.

Dataset Information

Msn2/4 regulate expression of glycolytic enzymes and control transition from quiescence to growth.

Publications

Msn2/4 regulate expression of glycolytic enzymes and control transition from quiescence to growth.

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