Metabolic reprogramming reshapes the tumor microenvironment(TME)and facilitates metastasis,but its molecular mechanisms remain incompletely understood.Here,we identified enolase 2(ENO2),a critical glycolytic enzyme,as...Metabolic reprogramming reshapes the tumor microenvironment(TME)and facilitates metastasis,but its molecular mechanisms remain incompletely understood.Here,we identified enolase 2(ENO2),a critical glycolytic enzyme,as being associated with lymphatic metastasis in head and neck squamous cell carci-noma(HNSCC).Mechanistically,phosphoenolpyruvate(PEP),the metabolite secreted by ENO2-expressing HNSCC cells,drove histone H3 lysine 18 lactylation(H3K18la)-mediated M2 polarization in macrophages,which,in turn,enhanced the epithelial-mesenchymal transition(EMT)and invasiveness of HNSCC cells.Pharmacological inhibition of ENO2 with POMHEX effectively reversed M2 macrophage polarization and inhibited HNSCC lymphatic metastasis.Collectively,our findings underscore the prog-nostic significance of ENO2 and highlight its potential as a therapeutic target for metastatic HNSCC.Furthermore,we reveal a previously underappreciated role of PEP in modulating the tumor immune microenvironment and tumor metastasis via epigenetic modification.展开更多
Metabolic reprogramming is a common phenomenon in cancer,with aerobic glycolysis being one of its important characteristics.Hypoxia-inducible factor-1α(HIF1Α)is thought to play an important role in aerobic glycolysi...Metabolic reprogramming is a common phenomenon in cancer,with aerobic glycolysis being one of its important characteristics.Hypoxia-inducible factor-1α(HIF1Α)is thought to play an important role in aerobic glycolysis.Meanwhile,naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits.In this work,we identified glycolytic genes related to HIF1Αby analyzing the colon cancer database.The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Αoverexpression on glycolysis,and the proliferation and migration of colon cancer cells.Moreover,naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Αfunction.The results showed that the HIF1Αand enolase 2(ENO2)levels in colon cancer tissues were highly correlated,and their high expression indicated a poor prognosis for colon cancer patients.Mechanistically,HIF1Αdirectly binds to the DNA promoter region and upregulates the transcription of ENO2;ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells.Most importantly,we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α,which in turn decreased aerobic glycolysis in colon cancer cells.Generally,naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Αand the proliferation and invasion of colon cancer cells.This study helps to elucidate the relationship between colon cancer progression and glucose metabolism,and demonstrates the efficacy of naringin in the treatment of colon cancer.展开更多
基金supported by grants from the National Natural Science Foundation of China(82204428,U24A20815,82304526,82204427,82201001,82430108,82293681(82293680),82273941)the National High-level Personnelof Special Support Program(to Dongmei Zhang and Minfeng Chen)+5 种基金the Natural Science Foundation of Guangdong Province(2023A1515010361 and 2022A1515011813)the Guangdong Basic and Applied Basic Research Foundation(2024B1515020098)the Science and Technology Program of Guangzhou(SL2024A04J00410,SL2024A04J00374,SL2024A04J00280)the Fundamental Research Funds for The Central Universities(21624103)the Science and Technology Projects in Guangzhou(2023A03J1030,202201010173,202102070001)the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(JNU1AF-CFTP-2022-a01210).
文摘Metabolic reprogramming reshapes the tumor microenvironment(TME)and facilitates metastasis,but its molecular mechanisms remain incompletely understood.Here,we identified enolase 2(ENO2),a critical glycolytic enzyme,as being associated with lymphatic metastasis in head and neck squamous cell carci-noma(HNSCC).Mechanistically,phosphoenolpyruvate(PEP),the metabolite secreted by ENO2-expressing HNSCC cells,drove histone H3 lysine 18 lactylation(H3K18la)-mediated M2 polarization in macrophages,which,in turn,enhanced the epithelial-mesenchymal transition(EMT)and invasiveness of HNSCC cells.Pharmacological inhibition of ENO2 with POMHEX effectively reversed M2 macrophage polarization and inhibited HNSCC lymphatic metastasis.Collectively,our findings underscore the prog-nostic significance of ENO2 and highlight its potential as a therapeutic target for metastatic HNSCC.Furthermore,we reveal a previously underappreciated role of PEP in modulating the tumor immune microenvironment and tumor metastasis via epigenetic modification.
基金supported by the Fund of Hubei Provincial Health Commission(No.ZY2021M080)the Medical Research Project of Jiangsu Provincial Health Commission(No.Z2021068)+1 种基金the Yancheng Medical Science and Technology Development Plan Project(No.YK2021004)the Young Scientific and Technological Talents Support Project by Jiangsu Association for Science and Technology(No.TJ-2022-097),China.
文摘Metabolic reprogramming is a common phenomenon in cancer,with aerobic glycolysis being one of its important characteristics.Hypoxia-inducible factor-1α(HIF1Α)is thought to play an important role in aerobic glycolysis.Meanwhile,naringin is a natural flavanone glycoside derived from grapefruits and many other citrus fruits.In this work,we identified glycolytic genes related to HIF1Αby analyzing the colon cancer database.The analysis of extracellular acidification rate and cell function verified the regulatory effects of HIF1Αoverexpression on glycolysis,and the proliferation and migration of colon cancer cells.Moreover,naringin was used as an inhibitor of colon cancer cells to illustrate its effect on HIF1Αfunction.The results showed that the HIF1Αand enolase 2(ENO2)levels in colon cancer tissues were highly correlated,and their high expression indicated a poor prognosis for colon cancer patients.Mechanistically,HIF1Αdirectly binds to the DNA promoter region and upregulates the transcription of ENO2;ectopic expression of ENO2 increased aerobic glycolysis in colon cancer cells.Most importantly,we found that the appropriate concentration of naringin inhibited the transcriptional activity of HIF1Α,which in turn decreased aerobic glycolysis in colon cancer cells.Generally,naringin reduces glycolysis in colon cancer cells by reducing the transcriptional activity of HIF1Αand the proliferation and invasion of colon cancer cells.This study helps to elucidate the relationship between colon cancer progression and glucose metabolism,and demonstrates the efficacy of naringin in the treatment of colon cancer.
