Long non-coding RNA VAL facilitates PKM2 enzymatic activity to promote glycolysis and malignancy of gastric cancer.


Journal

Clinical and translational medicine
ISSN: 2001-1326
Titre abrégé: Clin Transl Med
Pays: United States
ID NLM: 101597971

Informations de publication

Date de publication:
10 2022
Historique:
revised: 25 09 2022
received: 27 06 2022
accepted: 29 09 2022
entrez: 14 10 2022
pubmed: 15 10 2022
medline: 18 10 2022
Statut: ppublish

Résumé

Gastric cancer (GC) is one of the most common types of cancer worldwide, which leads to more than 10% of cancer-related deaths. Metabolism reprogramming presents as a pivotal event in cancer initiation and progression through enhancing aerobic glycolysis and anabolic metabolism. However, the underlying regulatory mechanisms in GC remain unknown. VAL was identified by bioinformatics analyses in GC. Cell-based assays and mouse model illustrate the role of VAL in GC. RNA pull-down, immunoprecipitation assay and Western blot elucidate the interaction between VAL and PKM2. Pyruvate kinase activity, ECAR and OCR were measured to validate aerobic glycolysis of GC cells. Long non-coding RNA (lncRNA) VAL is significantly upregulated in GCs and indicates poor prognosis. Functional assays showed that VAL promotes GC malignant progression. Mechanistically, VAL strengthens the enzymatic activity of PKM2 and aerobic glycolysis of GC cells through directly binding with PKM2 to abrogate the PKM2-Parkin interaction, and to suppress Parkin-induced polyubiquitination of PKM2. In addition, glucose starvation induces VAL expression to enhance this process. Our study provides an insight into an lncRNA-dependent regulation on the enzymatic activity of PKM2, and suggests a potential of targeting VAL or PKM2 as promising biomarkers in GC diagnosis and treatment.

Sections du résumé

BACKGROUND
Gastric cancer (GC) is one of the most common types of cancer worldwide, which leads to more than 10% of cancer-related deaths. Metabolism reprogramming presents as a pivotal event in cancer initiation and progression through enhancing aerobic glycolysis and anabolic metabolism. However, the underlying regulatory mechanisms in GC remain unknown.
METHODS
VAL was identified by bioinformatics analyses in GC. Cell-based assays and mouse model illustrate the role of VAL in GC. RNA pull-down, immunoprecipitation assay and Western blot elucidate the interaction between VAL and PKM2. Pyruvate kinase activity, ECAR and OCR were measured to validate aerobic glycolysis of GC cells.
RESULTS
Long non-coding RNA (lncRNA) VAL is significantly upregulated in GCs and indicates poor prognosis. Functional assays showed that VAL promotes GC malignant progression. Mechanistically, VAL strengthens the enzymatic activity of PKM2 and aerobic glycolysis of GC cells through directly binding with PKM2 to abrogate the PKM2-Parkin interaction, and to suppress Parkin-induced polyubiquitination of PKM2. In addition, glucose starvation induces VAL expression to enhance this process.
CONCLUSIONS
Our study provides an insight into an lncRNA-dependent regulation on the enzymatic activity of PKM2, and suggests a potential of targeting VAL or PKM2 as promising biomarkers in GC diagnosis and treatment.

Identifiants

pubmed: 36229913
doi: 10.1002/ctm2.1088
pmc: PMC9561166
doi:

Substances chimiques

Carrier Proteins 0
Membrane Proteins 0
RNA, Long Noncoding 0
Thyroid Hormones 0
Ubiquitin-Protein Ligases EC 2.3.2.27
Pkm protein, mouse EC 2.7.1.40
Pyruvate Kinase EC 2.7.1.40
Glucose IY9XDZ35W2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e1088

Informations de copyright

© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Références

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33.
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115-132.
Chen W, Sun K, Zheng R, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res. 2018;30(1):1-12.
Sano T. Gastric cancer: Asia and the world. Gastric Cancer. 2017;20(1):1-2.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008;7(1):11-20.
Mikawa T, LL ME, Takaori-Kondo A, Inagaki N, Yokode M, Kondoh H. Dysregulated glycolysis as an oncogenic event. Cell Mol Life Sci. 2015;72(10):1881-1892.
Dong Y, Tu R, Liu H, Qing G. Regulation of cancer cell metabolism: oncogenic MYC in the driver's seat. Signal Transduct Target Ther. 2020;5(1):124.
Bao X, Zhang J, Huang G, et al. The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis. 2021;12(2):215.
Gao P, Sun L, He X, Cao Y, Zhang H. MicroRNAs and the Warburg effect: new players in an old arena. Curr Gene Ther. 2012;12(4):285-291.
Sawant Dessai A, Kalhotra P, Novickis AT, Dasgupta S. Regulation of tumor metabolism by post translational modifications on metabolic enzymes. Cancer Gene Ther. 2022. http://doi.org/10.1038/s41417-022-00521-x
Hitosugi T, Chen J. Post-translational modifications and the Warburg effect. Oncogene. 2014;33(34):4279-4285.
Shankaraiah RC, Veronese A, Sabbioni S, Negrini M. Non-coding RNAs in the reprogramming of glucose metabolism in cancer. Cancer Lett. 2018;419:167-174.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033.
Ashizawa K, Willingham MC, Liang CM, SY Cheng. In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate. J Biol Chem. 1991;266(25):16842-16846.
Zahra K, Dey T, Ashish, Mishra SP, Pandey U. Pyruvate kinase M2 and cancer: the role of PKM2 in promoting tumorigenesis. Front Oncol. 2020;10:159.
Zhu S, Guo Y, Zhang X, et al. Pyruvate kinase M2 (PKM2) in cancer and cancer therapeutics. Cancer Lett. 2021;503:240-248.
Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47-62.
Schmitt AM, Chang HY. Long noncoding RNAs in cancer pathways. Cancer Cell. 2016;29(4):452-463.
Gupta RA, Shah N, Wang KC, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071-1076.
Liu B, Sun L, Liu Q, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27(3):370-381.
Kretz M, Siprashvili Z, Chu C, et al. Control of somatic tissue differentiation by the long non-coding RNA TINCR. Nature. 2013;493(7431):231-235.
Tseng YY, Moriarity BS, Gong W, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512(7512):82-86.
Zhou XY, Yin CQ, Dang YN, Ye F, Zhang GX. Identification of the long non-coding RNA H19 in plasma as a novel biomarker for diagnosis of gastric cancer. Sci Rep. 2015;5:11516.
Quagliata L, Matter MS, Piscuoglio S, et al. Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients. Hepatology. 2014;59(3):911-923.
Bussemakers MJ, van Bokhoven A, Verhaegh GW, et al. DD3: a new prostate-specific gene, highly overexpressed in prostate cancer. Cancer Res. 1999;59(23):5975-5979.
Zhu Y, Jin L, Shi R, et al. The long noncoding RNA glycoLINC assembles a lower glycolytic metabolon to promote glycolysis. Mol Cell. 2022;82(3):542-554.e6.
Zheng F, Chen J, Zhang X, et al. The HIF-1alpha antisense long non-coding RNA drives a positive feedback loop of HIF-1alpha mediated transactivation and glycolysis. Nat Commun. 2021;12(1):1341.
Dong P, Xiong Y, Konno Y, et al. Long non-coding RNA DLEU2 drives EMT and glycolysis in endometrial cancer through HK2 by competitively binding with miR-455 and by modulating the EZH2/miR-181a pathway. J Exp Clin Cancer Res. 2021;40(1):216.
Guan YF, Huang QL, Ai YL, et al. Nur77-activated lncRNA WFDC21P attenuates hepatocarcinogenesis via modulating glycolysis. Oncogene. 2020;39(11):2408-2423.
Hua Q, Jin M, Mi B, et al. LINC01123, a c-Myc-activated long non-coding RNA, promotes proliferation and aerobic glycolysis of non-small cell lung cancer through miR-199a-5p/c-Myc axis. J Hematol Oncol. 2019;12(1):91.
Xing Z, Zhang Y, Liang K, et al. Expression of long noncoding RNA YIYA promotes glycolysis in breast cancer. Cancer Res. 2018;78(16):4524-4532.
Tian H, Lian R, Li Y, et al. AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent vimentin degradation. Nat Commun. 2020;11(1):5127.
Liu K, Li F, Han H, et al. Parkin regulates the activity of pyruvate kinase M2. J Biol Chem. 2016;291(19):10307-10317.
Yu S, Zang W, Qiu Y, Liao L, Zheng X. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. Oncogene. 2022;41(1):46-56.
Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703-707.
Lee HJ, Li CF, Ruan D, et al. Non-proteolytic ubiquitination of hexokinase 2 by HectH9 controls tumor metabolism and cancer stem cell expansion. Nat Commun. 2019;10(1):2625.
Feng Y, Zhang Y, Cai Y, et al. A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma. Cell Death Dis. 2020;11(2):89.
Han C, Yang L, Choi HH, et al. Amplification of USP13 drives ovarian cancer metabolism. Nat Commun. 2016;7:13525.
Wang C, Chao Y, Xu W, Liu Z, Wang H, Huang K. Myeloid FBW7 deficiency disrupts redox homeostasis and aggravates dietary-induced insulin resistance. Redox Biol. 2020;37:101688.
Viana R, Lujan P, Sanz P. The laforin/malin E3-ubiquitin ligase complex ubiquitinates pyruvate kinase M1/M2. BMC Biochem. 2015;16:24.
Ding H, Wang JJ, Zhang XY, Yin L, Feng T. Lycium barbarum polysaccharide antagonizes LPS-induced inflammation by altering the glycolysis and differentiation of macrophages by triggering the degradation of PKM2. Biol Pharm Bull. 2021;44(3):379-388.
Sun T, Liu Z, Bi F, Yang Q. Deubiquitinase PSMD14 promotes ovarian cancer progression by decreasing enzymatic activity of PKM2. Mol Oncol. 2021;15(12):3639-3658.
Wong N, Ojo D, Yan J, Tang D. PKM2 contributes to cancer metabolism. Cancer Lett. 2015;356(2 Pt A):184-191.
Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function and expression and regulation. Cell Biosci. 2019;9:52.
Jordheim LP, Durantel D, Zoulim F, Dumontet C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov. 2013;12(6):447-464.

Auteurs

Ting Dai (T)

Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, China.
GMU-GIBH Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.

Xin Zhang (X)

Clinical Experimental Center, Jiangmen Key Laboratory of Clinical Biobanks and Translational Research, Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China.

Xiang Zhou (X)

Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Xiaoxia Hu (X)

Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, China.

Xiaodi Huang (X)

Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, China.

Feiyue Xing (F)

Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, China.

Han Tian (H)

Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Yun Li (Y)

Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, Guangdong, China.

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