YEATS2 is a target of HIF1α and promotes pancreatic cancer cell proliferation and migration

Zeng, Zhirui; Lei, Shan; He, Zhiwei; Chen, Tengxiang; Jiang, Jianxin

doi:10.1002/jcp.29995

Cited by 36 publications

(24 citation statements)

References 27 publications

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“…Similarly, Overexpression of hydroxyproline via EGLN/HIF1A is associated with distant metastasis in PC [31]. Similarly, our early study also demonstrated that YEATS2 directly targets HIF1α which promotes PC cellS proliferation and mobility [32]. In the present study, we provided the rst evidences that FUT11 was a novel target gene of HIF1α, which involved in the biology function mediating by HIF1α under hypoxia.…”

Section: Discussionsupporting

confidence: 65%

Hypoxia-Related Gene FUT11 Promoted Pancreatic Cancer Progression Via Maintaining The Stabilization of PDK1

Cao

Zeng

et al. 2021

Preprint

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Background: Hypoxia participated in the occurrence and development of pancreatic cancer (PC). However, genes associated with hypoxia respond and their regulated mechanism in PC cells were unclear. The current research was aimed to illuminate the role and hypoxia regulated mechanism of fucosyltransferase 11 (FUT11) in the progression of PC.Methods: After predicting FUT11 as a key hypoxia associated gene in PC using bioinformatics analysis. The expression of FUT11 in PC using quantitative real-time fluorescent PCR, western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation, migration and invasion under normoxia and hypoxia were detected using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine assay, colony formation assay and transwell assay. Spleen capsule injected liver metastasis and subcutaneously injected model were performed to confirm the effects of FUT11 in vivo. Furthermore, western blot, luciferase assay and immunoprecipitation were performed to explore the regulated relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC.Results: FUT11 was markedly increased of PC cells in hypoxia, up-regulated in the PC clinical tissues, and predicted a poor outcome. Inhibition of FUT11 reduced PC cell growth and mobility of PC cells under normoxia and hypoxia conditions in vitro, and growth and mobility in vivo. FUT11 bind with PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 knockdown significantly increased the degradation rate of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressiv impacts of FUT11 knockdown on PC cell growth and mobility. In addition, HIF1α bound to the enhancer of FUT11 and increased its expression, as well as co-expressing with FUT11 in PC tissues. Furthermore, overexpress of FUT11 partially rescued the suppressiv effects of HIF1α knockdown on PC cell growth and mobility in hypoxia conditions.Conclusion: Our data further implicate that hypoxia-induced FUT11 in PC contributes to proliferation and metastasis by maintaining the stability of PDK1, and suggest FUT11 maybe a novel and effective target for treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 65%

Hypoxia-Related Gene FUT11 Promoted Pancreatic Cancer Progression Via Maintaining The Stabilization of PDK1

Cao

Zeng

et al. 2021

Preprint

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“…Similarly, overexpression of hydroxyproline via EGLN/HIF1A is associated with distant metastasis in PC (30). Similarly, our previous study also demonstrated that YEATS2 directly targets HIF1a which promotes PC cell proliferation and mobility (31).…”

Section: Discussionsupporting

confidence: 52%

Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

Cao

Zeng

Pan³

et al. 2021

Front. Oncol.

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BackgroundHypoxia is associated with the development of pancreatic cancer (PC). However, genes associated with hypoxia response and their regulatory mechanism in PC cells were unclear. The current study aims to investigate the role of the hypoxia associated gene fucosyltransferase 11 (FUT11) in the progression of PC.MethodsIn the preliminary study, bioinformatics analysis predicted FUT11 as a key hypoxia associated gene in PC. The expression of FUT11 in PC was evaluated using quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry. The effects of FUT11 on PC cells proliferation and migration under normoxia and hypoxia were evaluated using Cell Counting Kit 8, 5-ethynyl-2’-deoxyuridine (EDU) assay, colony formation assay and transwell assay. The effects of FUT11 in vivo was examined in mouse tumor models of liver metastasis and subcutaneous xenograft. Furthermore, Western blot, luciferase assay and immunoprecipitation were performed to explore the regulatory relationship among FUT11, hypoxia-inducible factor 1α (HIF1α) and pyruvate dehydrogenase kinase 1 (PDK1) in PC.ResultsFUT11 was markedly increased of PC cells with hypoxia, upregulated in the PC clinical tissues, and predicted a poor outcome of PC patients. Inhibition of FUT11 reduced PC cell growth and migratory ability of PC cells under normoxia and hypoxia conditions in vitro, and growth and tumor cell metastasis in vivo. FUT11 bound to PDK1 and regulated the expression PDK1 under normoxia and hypoxia. FUT11 interacted with PDK1 and decreased the ubiquitination of PDK1, lead to the activation of AKT/mTOR signaling pathway. FUT11 knockdown significantly increased the degradation of PDK1 under hypoxia, while treatment with MG132 can relieve the degradation of PDK1 induced by FUT11 knockdown. Overexpression of PDK1 in PC cells under hypoxia conditions reversed the suppressive impacts of FUT11 knockdown on PC cell growth and migration. In addition, HIF1α bound to the promoter of FUT11 and increased its expression, as well as co-expressed with FUT11 in PC tissues. Furthermore, overexpression of FUT11 partially rescued the suppressive effects of HIF1α knockdown on PC cell growth and migration in hypoxia condition.ConclusionOur data implicate that hypoxia-induced FUT11 contributes to proliferation and metastasis of PC by maintaining the stability of PDK1, thus mediating activation of AKT/mTOR signaling pathway, and suggest that FUT11 could be a novel and effective target for the treatment of pancreatic cancer.

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“…The YEATS domain containing 2 (YEATS2) protein is a selective histone crotonylation reader that regulates the activity of histone deacetylases. HIF-1α increases YEATS2 expression via binding to its hypoxia response element (HRE) to promote the proliferation and migration of PC cells under hypoxia [145]. Moreover, HIF-1α mediates transcriptional activation of urokinase-type plasminogen activator receptor (uPAR) and uPAR-dependent angioinvasion, which is critical for hypoxia-induced metastasis [146].…”

Section: Emt Invasion Migration and Metastasis Under Hypoxiamentioning

confidence: 99%

Targeting hypoxic tumor microenvironment in pancreatic cancer

et al. 2021

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Attributable to its late diagnosis, early metastasis, and poor prognosis, pancreatic cancer remains one of the most lethal diseases worldwide. Unlike other solid tumors, pancreatic cancer harbors ample stromal cells and abundant extracellular matrix but lacks vascularization, resulting in persistent and severe hypoxia within the tumor. Hypoxic microenvironment has extensive effects on biological behaviors or malignant phenotypes of pancreatic cancer, including metabolic reprogramming, cancer stemness, invasion and metastasis, and pathological angiogenesis, which synergistically contribute to development and therapeutic resistance of pancreatic cancer. Through various mechanisms including but not confined to maintenance of redox homeostasis, activation of autophagy, epigenetic regulation, and those induced by hypoxia-inducible factors, intratumoral hypoxia drives the above biological processes in pancreatic cancer. Recognizing the pivotal roles of hypoxia in pancreatic cancer progression and therapies, hypoxia-based antitumoral strategies have been continuously developed over the recent years, some of which have been applied in clinical trials to evaluate their efficacy and safety in combinatory therapies for patients with pancreatic cancer. In this review, we discuss the molecular mechanisms underlying hypoxia-induced aggressive and therapeutically resistant phenotypes in both pancreatic cancerous and stromal cells. Additionally, we focus more on innovative therapies targeting the tumor hypoxic microenvironment itself, which hold great potential to overcome the resistance to chemotherapy and radiotherapy and to enhance antitumor efficacy and reduce toxicity to normal tissues.

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YEATS2 is a target of HIF1α and promotes pancreatic cancer cell proliferation and migration

Cited by 36 publications

References 27 publications

Hypoxia-Related Gene FUT11 Promoted Pancreatic Cancer Progression Via Maintaining The Stabilization of PDK1

Hypoxia-Related Gene FUT11 Promoted Pancreatic Cancer Progression Via Maintaining The Stabilization of PDK1

Hypoxia-Related Gene FUT11 Promotes Pancreatic Cancer Progression by Maintaining the Stability of PDK1

Targeting hypoxic tumor microenvironment in pancreatic cancer

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