Transcriptional activation of SIRT6 via FKHRL1/FOXO3a inhibits the Warburg effect in glioblastoma cells

Dong, Zhen; Zhong, Xiaoxia; Lei, Qian; Chen, Fei; Cui, Hongjuan

doi:10.1016/j.cellsig.2019.04.009

Cited by 23 publications

(20 citation statements)

References 49 publications

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“…However, in the hypoxic tumor microenvironment, where energy demand is very high, pyruvate is metabolized into lactate acid via anaerobic glycolysis, and glucose uptake is enhanced to increase the ATP production in tumor cells 61–63 . To block glycolytic activity during HCC treatment, there are three strategies: (1) using inhibitors of glucose transporters 63,64 , (2) using inhibitors targeting hypoxia-associated pathways 11,65–67 , and (3) inhibitors of LDHA 68 to ameliorate the accumulation of lactic acid. Hypersynthesis of fatty acid in HCC cells is driving glucose uptake 61–65 .…”

Section: Discussionmentioning

confidence: 99%

SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

et al. 2019

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Lipid metabolism that correlates tightly to the glucose metabolic regulation in malignant cells includes hepatocellular carcinoma (HCC) cells. The transcription factor Sterol Regulatory Element Binding Protein 1 (SREBP-1), a regulator of fatty acid synthesis, has been shown to pivotally regulate the proliferation and metastasis of HCC cells. However, the intrinsic mechanism by which SREBP-1 regulates the survival of HCC cells remains unclear. In this study, among HCC patients who had dismal responses to Sorafenib, a high SREBP-1 level was found in the tumors and correlated to poor survival. This observation suggested the negative role of SREBP-1 in clinical HCC prognosis. Our mechanistical studies reveal that the inhibition of SREBP-1 via its inhibitor Betulin suppresses cellular glucose metabolism. In addition to the reduced glycolytic activity, a thwarted metastatic potential was observed in HCC cells upon Betulin administration. Moreover, our data show that SREBP-1 inhibition facilitated the antitumor effects of Sorafenib on HCC cells and xenograft tumors.

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Section: Discussionmentioning

confidence: 99%

SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

et al. 2019

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“…Additionally, FOXO3A was recently shown to be negatively correlated with the expression of a number of glycolysis-associated genes and to inhibit glucose metabolism and tumor cell proliferation in melanoma (54). Furthermore, transcriptional activation of FOXO3A inhibits the Warburg effect in glioblastoma cells (55). Together these studies suggest that FOXO3A is associated with the Warburg effect, which warrants further investigation.…”

Section: Discussionmentioning

confidence: 91%

Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient‑derived organoids

et al. 2020

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Enhancing the radioresponsiveness of colorectal cancer (CRC) is essential for local control and prognosis. However, consequent damage to surrounding healthy cells can lead to treatment failure. We hypothesized that short-chain fatty acids (SCFAs) could act as radiosensitizers for cancer cells, allowing the administration of a lower and safer dose of radiation. To test this hypothesis, the responses of three-dimensional-cultured organoids, derived from CRC patients, to radiotherapy, as well as the effects of combined radiotherapy with the SCFAs butyrate, propionate and acetate as candidate radiosensitizers, were evaluated via reverse transcription-quantitative polymerase chain reaction, immunohistochemistry and organoid viability assay. Of the three SCFAs tested, only butyrate suppressed the proliferation of the organoids. Moreover, butyrate significantly enhanced radiation-induced cell death and enhanced treatment effects compared with administration of radiation alone. The radiation-butyrate combination reduced the proportion of Ki-67 (proliferation marker)-positive cells and decreased the number of S phase cells via FOXO3A. Meanwhile, 3/8 CRC organoids were found to be non-responsive to butyrate with lower expression levels of FOXO3A compared with the responsive cases. Notably, butyrate did not increase radiation-induced cell death and improved regeneration capacity after irradiation in normal organoids. These results suggest that butyrate could enhance the efficacy of radiotherapy while protecting the normal mucosa, thus highlighting a potential strategy for minimizing the associated toxicity of radiotherapy.

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“…Results were calculated via the 2 -∆∆Cq method (25) with ACTB expression used as the internal control (Cq value was used instead of Ct value in this study). The primers, which were also used in a previous study (14), were presented in Table I.…”

Section: Reverse Transcription-quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

“…Glucose stress flux test. A glucose stress flux test was conducted as previously reported (14). In brief, 40,000 cells were seeded into XF96 cell culture microplates and cultured at 37˚C for 24 h. The medium was then replaced with Seahorse XF DMEM (Agilent Technologies, Inc.) containing 2 µM glutamine, and the microplates were maintained in a non-CO 2 incubator at 37˚C for 60 min.…”

Section: Western Blot Assaymentioning

confidence: 99%

“…Forkhead box O (FOXO) transcription factors, including FOXO1, FOXO3a, FOXO4 and FOXO6, which are conserved from Caenorhabditis elegans to mammals, serve pivotal roles in multiple cellular processes, such as cell cycle progression, apoptotic cell death, DNA repair, oxidative stress, epithelial-mesenchymal transition and cellular metabolism (10)(11)(12)(13). FOXO3a, an important member of the FOXO family, participates into the modulation of cell growth in multiple tumors, including glioblastoma (14), prostate cancer (15), lung adenocarcinoma (16), ovarian cancer (17), colorectal cancer (18) and Hodgkin's lymphoma (19). It was reported that FOXO3a is also an important regulator of cellular metabolism in tumors; for example, FOXO3a regulates reactive oxygen metabolism by inhibiting mitochondrial gene expression in colon cancer (20).…”

Section: Introductionmentioning

confidence: 99%

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FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

Dong

Yang

et al. 2020

Int J Oncol

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Melanoma, the most aggressive human skin tumor, has a very short survival time, and there are currently no effective treatments. Alterations in cell metabolism, such as enhanced aerobic glycolysis, have been identified as hallmarks of cancer cells. In the present study, bioinformatics studies using online databases revealed that FOXO3a expression was lower in melanoma tissues compared with normal tissues and nevus. Additionally, Kaplan-Meier analysis showed that high expression of FOXO3a predicted an improved prognosis for patients with melanoma. Furthermore, Pearson correlation analysis indicated that the expression of FOXO3a was positively correlated with SIRT6 expression and negatively correlated with the expression levels of a number of glycolysis-associated genes. Chromatin immunoprecipitation and luciferase assays showed that FOXO3a was enriched in the SIRT6 promoter region and promoted its transcription. Then, SIRT6 was overexpressed in FOXO3a-knockdown MV3 cells and downregulated in FOXO3a-overexpressing MV3 cells by using lentivirus-mediated stable infection. The results showed that SIRT6 knockdown or overexpression rescued the effects of FOXO3a overexpression or knockdown, respectively, on glycolysis, as determined by glucose uptake, glucose consumption and lactate production assays, the expression of glycolytic genes and glucose stress flux tests. SIRT6 overexpression also suppressed FOXO3a knockdown-induced tumor growth in a mouse model. The present findings indicated that the FOXO3a-SIRT6 regulatory axis inhibited glucose metabolism and tumor cell proliferation in melanoma, and provided novel insight into potential therapeutic strategies to treat this disease.

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Transcriptional activation of SIRT6 via FKHRL1/FOXO3a inhibits the Warburg effect in glioblastoma cells

Cited by 23 publications

References 49 publications

SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

SREBP-1 inhibitor Betulin enhances the antitumor effect of Sorafenib on hepatocellular carcinoma via restricting cellular glycolytic activity

Butyrate enhances the efficacy of radiotherapy via FOXO3A in colorectal cancer patient‑derived organoids

FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma

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