FOXK1 and FOXK2 regulate aerobic glycolysis

Sukonina, Valentina; Ma, Hua; Zhang, Wei; Bartesaghi, Stefano; Subhash, Santhilal; Heglind, Mikael; Foyn, Håvard; Betz, Matthias Johannes; Nilsson, Daniel; Lidell, Martin E.; Naumann, Jennifer; Haufs-Brusberg, Saskia; Palmgren, Henrik; Mondal, Tanmoy; Beg, Muheeb; Jedrychowski, Mark P.; Taskén, Kjetil; Pfeifer, Alexander; Peng, Xiaorong; Kanduri, Chandrasekhar; Enerbäck, Sven

doi:10.1038/s41586-019-0900-5

Cited by 119 publications

(106 citation statements)

References 51 publications

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“…The AKT/mTOR signaling pathway has been demonstrated to be involved in the proliferation and metabolism of cells, thus playing an important role in the occurrence and development of cancers (23). Moreover, recent studies found that FOXK1 was enrolled in regulating metabolism (20). Therefore, we investigated whether FOXK1 exerts the tumor-promoting functions via Akt/mTOR signaling pathway.…”

Section: Foxk1 Promotes Gbc Cells Migration and Invasion In Vitro Andmentioning

confidence: 97%

“…Meanwhile, dysregulation of FOX proteins has been reported to promote the development and progress of disorders, especially carcinogenesis (16,17). Forkhead box k1 (FOXK1), a member of the FOX transcription factor family, has been reported to play pivotal roles in cell cycle control (18), cell signaling (19), and cell metabolism (20). Recently, accumulating evidences showed that FOXK1 was upregulated in various tumor tissues and might participate in the tumorigenesis (19,21).…”

Section: Introductionmentioning

confidence: 99%

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FOXK1 Promotes Proliferation and Metastasis of Gallbladder Cancer by Activating AKT/mTOR Signaling Pathway

Wang

et al. 2020

Front. Oncol.

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Gallbladder cancer (GBC) is one of the most lethal malignancies worldwide, with extremely poor prognosis. Recently, forkhead box k1 (FOXK1), a member of the FOX transcription factor family, has been reported to be correlated with tumor progression in multiple malignancies. However, the role of FOXK1 in GBC has not been elucidated. In this study, we demonstrated that the expression level of FOXK1 was elevated in human GBC tissues and associated with increased liver metastasis, poor histological differentiation, advanced TNM stage, and shorter overall survival. Knockdown of FOXK1 expression inhibited GBC cells proliferation and metastasis. Consistently, overexpression of FOXK1 promoted GBC cells progression. Mechanical investigations verified that knockdown of FOXK1 could lead to G1/S cell cycle arrest through downregulating CDK4, CDK6, cyclin D1, and cyclin E1. And FOXK1 could regulate the expression of epithelial-mesenchymal transition (EMT) related proteins E-cad, N-cad, and Vimentin. Moreover, we found that FOXK1 could regulate the activation of Akt/mTOR signaling pathway. In addition, AKT special inhibitor MK-2206 could abolish the proliferation and metastasis discrepancy between FOXK1 overexpression GBC cells and control cells, which suggested the tumorpromoting effect of FOXK1 may be partially related with the activations of Akt/mTOR signaling pathway. Collectively, our results suggested that FOXK1 promotes GBC cells progression and represent a novel prognostic biomarker and potential therapeutic target in GBC.

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Section: Foxk1 Promotes Gbc Cells Migration and Invasion In Vitro Andmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

FOXK1 Promotes Proliferation and Metastasis of Gallbladder Cancer by Activating AKT/mTOR Signaling Pathway

Wang

et al. 2020

Front. Oncol.

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“…Previous studies have identified a crucial role of FOXK1 in cancers [33][34][35]. To explore whether HUMT exerted its function through FOXK1-mediated cell proliferation and vascular endothelial growth factor (VEGFC) signaling, which was a previously reported key lymphangiogenesis pathway [36,37], we analyzed the effect of HUMT-KO by western blot.…”

Section: Foxk1 Is Crucial To Humt-mediated Cell Proliferation Metastmentioning

confidence: 99%

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

et al. 2020

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Background: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied. Methods: The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT. Results: HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis. Conclusions: Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.

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“…In contrast, the pyruvate dehydrogenase levels was higher in SEMA3F KD groups, but Pyruvate kinase isozymes M2(PKM2) expression levels was not difference between two groups. These results suggested that level of aerobic glycolysis of LECs in SEMA3F KD groups was lower than that in control groups in hypoxia, it converted glycolysis to the Krebs cycle was not be blocked(Liu et al ,2017;DeWaal et al ,2018; Sukonina et al ,2019). To further determination the efficacy to knock down SEMA3F of CRCs inhibition glycolysis of hLECs in hypoxia, therefore, we use 3-bromopyruvate to inhibit the glycolysis of the two groups.…”

Section: Resultsmentioning

confidence: 84%

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

Tao

et al. 2019

Preprint

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22 30 tubulogenesis capacity and hLECs migration were escalated in the 31 hypoxia, the hLECs mainly relied on fatty acid metabolism not aerobic 32 glycolysis during lymphangiogenesis. SEMA3F-deficient CRCs 33 up-regulated PMAKP expression and phosphorylation of hLECs, and 34 activated its peroxisome proliferator-activated receptor (PPARs) and 35 Peroxisome proliferator-activated receptor gamma coactivator-1 alpha 36 (PGC-1a) facilitated their switched toward fatty acids (FA) catabolism. 37Furthermore, we observed that activation of the PGCI-PPAR lipid 38 oxidation signaling pathway in hLECs was caused by the secretion of 39 interleukin-6 by tumor cells.Taken together, this study indicates that 40 CRCs with SEMA3F expression depletion significantly promotes 41 lymphangiogenesis in hypoxia and faciliates the secretion of IL-6 in 42 tumor cell, and activates mitochondria fatty acids oxidation (FAO) 43 reaction in the hLECs by PGCI-PPAR signaling pathways to support its 44 growth. 45 46 acid metabolism; hypoxia 48 49 104 CRCs promotion hLECs lipid metabolism and lymphangiogenesis under 105 hypoxemia.We demonstrated that SEMA3F plays a crucial role in hLECs 106 energy metabolism. CRCs with SEMA3F expression depletion 107 significantly promotes hLECs migration and tubulogenesis capacity in 108 hypoxia, and enhance the lipid metabolism via suppressing aerobic 109 glycolysis of hLECs, and the lipid metabolism to induce the PGCI-PPAR 110 signaling pathway in hLECs. Further evidence demonstrated that CRCs 111 cell with SEMA3F expression depletion up-regulated its IL-6 secretion, 112 to activate the PGCI-PPAR signaling pathway and induces the lipid 113 metabolismin of hLECs in hypoxia. Our findings for the first time 114 revealed a novel role and the underlying mechanism, the CRCs cell with 115 SEMA3F expression deficiency was involved the energy metabolism 116 with hLECs in the hypoxia environment, and induce tumor 117 lymphangiogenesis of CRCs to promote lymphatic metastasis. 118 119 Result 120 1.SEMA 3F-deficient CRCs further enhance lymphangiogenesis 121 under hypoxic conditions 122 In our previous study, loss of SEMA3F expression, the inhibitory ligand 123 of NRP2, critically contributes to CRCs metastasis and 124 lymphangiogenesis in normoxia(Wu et al, 2011; Ou et al, 2015). To 125 examine whether SEMA3F loss expression plays any roles in induce 126 lymphangiogenesis of colorectal cancer cell in hypoxia, We used 127 supernatants of the colorectal adenocarcinoma cell line HCT116 with 128 SEMA3F expression and SEMA3F knockout (SEMA3F KD), to culture 129 hLECs three-dimensionally on matrigel substrate under normoxia and 130 hypoxia to induce tubule formation of hLECs. The tubulogenesis of 131 hLECs was improved in hypoxia than that in normoxia (p < 0.001; Figure 132 1A and B). Strikingly, comparing with control cells, SEMA3F KD groups 133 displayed significantly enhancement of tubulogenesis ability of hLECs 134 under normoxic conditions. Consistent with normoxic conditions 135 culture, SEMA3F KD groups had stronger abili...

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FOXK1 and FOXK2 regulate aerobic glycolysis

Cited by 119 publications

References 51 publications

FOXK1 Promotes Proliferation and Metastasis of Gallbladder Cancer by Activating AKT/mTOR Signaling Pathway

FOXK1 Promotes Proliferation and Metastasis of Gallbladder Cancer by Activating AKT/mTOR Signaling Pathway

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer

SEMA3F-deficient colorectal cancer cells Promote lymphangiogenesis: fatty acid metabolism replace glycolysis for energy supply during lymphatic endothelial cells proliferation in tumor hypoxia microenvironment

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