CARM1 Suppresses Serine Synthesis by Promoting PKM2 Activity

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Aug 23

PMID 30131339

Citations 12

Authors

Tharindumala Abeywardana

Myungeun Oh

Lei Jiang

Ying Yang

Mei Kong

Jikui Song

Yanzhong Yang

Affiliations

Soon will be listed here.

Abstract

Glucose is a critical nutrient for cell proliferation. However, the molecular pathways that regulate glucose metabolism are still elusive. We discovered that co-activator-associated arginine methyltransferase 1 (CARM1) suppresses glucose metabolism toward serine biosynthesis. By tracing the C-labeled glucose, we found that knockout mouse embryonic fibroblasts exhibit significantly increased serine synthesis than WT cells. This is caused, at least in part, by the reduced pyruvate kinase (PK) activity in these cells. The M2 isoform of PK (PKM2) is arginine-methylated by CARM1, and methylation enhances its activity. Mechanistically, CARM1 methylates PKM2 at arginines 445 and 447, which enhances PKM2 tetramer formation. Consequently, knockout cells exhibit significant survival advantages over WT cells when extracellular serine is limited, likely due to their enhanced serine synthesis capacity. Altogether, we identified CARM1 as an important regulator of glucose metabolism and serine synthesis.

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References

Vander Heiden M, Locasale J, Swanson K, Sharfi H, Heffron G, Amador-Noguez D . Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010; 329(5998):1492-9. PMC: 3030121. DOI: 10.1126/science.1188015. View

Israelsen W, Vander Heiden M . Pyruvate kinase: Function, regulation and role in cancer. Semin Cell Dev Biol. 2015; 43:43-51. PMC: 4662905. DOI: 10.1016/j.semcdb.2015.08.004. View

Huang L, Wang Z, Narayanan N, Yang Y . Arginine methylation of the C-terminus RGG motif promotes TOP3B topoisomerase activity and stress granule localization. Nucleic Acids Res. 2018; 46(6):3061-3074. PMC: 5888246. DOI: 10.1093/nar/gky103. View

Kung C, Hixon J, Choe S, Marks K, Gross S, Murphy E . Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol. 2012; 19(9):1187-98. PMC: 3775715. DOI: 10.1016/j.chembiol.2012.07.021. View

Cheng H, Qin Y, Fan H, Su P, Zhang X, Zhang H . Overexpression of CARM1 in breast cancer is correlated with poorly characterized clinicopathologic parameters and molecular subtypes. Diagn Pathol. 2013; 8:129. PMC: 3766166. DOI: 10.1186/1746-1596-8-129. View

Gosalvez M, Montalvo A, WEINHOUSE S . Stimulation of tumor-cell respiration by inhibitors of pyruvate kinase. Eur J Biochem. 1975; 55(1):315-21. DOI: 10.1111/j.1432-1033.1975.tb02165.x. View

Bedford M, Clarke S . Protein arginine methylation in mammals: who, what, and why. Mol Cell. 2009; 33(1):1-13. PMC: 3372459. DOI: 10.1016/j.molcel.2008.12.013. View

Parnell K, Foulks J, Nix R, Clifford A, Bullough J, Luo B . Pharmacologic activation of PKM2 slows lung tumor xenograft growth. Mol Cancer Ther. 2013; 12(8):1453-60. DOI: 10.1158/1535-7163.MCT-13-0026. View

Anastasiou D, Yu Y, Israelsen W, Jiang J, Boxer M, Hong B . Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol. 2012; 8(10):839-47. PMC: 3711671. DOI: 10.1038/nchembio.1060. View

10.

Sanchez G, Bondy-Chorney E, Laframboise J, Paris G, Didillon A, Jasmin B . A novel role for CARM1 in promoting nonsense-mediated mRNA decay: potential implications for spinal muscular atrophy. Nucleic Acids Res. 2015; 44(6):2661-76. PMC: 4824080. DOI: 10.1093/nar/gkv1334. View

11.

Wang L, Zhao Z, Meyer M, Saha S, Yu M, Guo A . CARM1 methylates chromatin remodeling factor BAF155 to enhance tumor progression and metastasis. Cancer Cell. 2014; 25(1):21-36. PMC: 4004525. DOI: 10.1016/j.ccr.2013.12.007. View

12.

Li S, Ali S, Duan X, Liu S, Du J, Liu C . JMJD1B Demethylates H4R3me2s and H3K9me2 to Facilitate Gene Expression for Development of Hematopoietic Stem and Progenitor Cells. Cell Rep. 2018; 23(2):389-403. PMC: 5933860. DOI: 10.1016/j.celrep.2018.03.051. View

13.

Wang Y, Zhou W, Wang J, Huang X, Zuo Y, Wang T . Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer. Mol Cell. 2016; 64(4):673-687. DOI: 10.1016/j.molcel.2016.09.028. View

14.

Gao X, Wang H, Yang J, Liu X, Liu Z . Pyruvate kinase M2 regulates gene transcription by acting as a protein kinase. Mol Cell. 2012; 45(5):598-609. PMC: 3299833. DOI: 10.1016/j.molcel.2012.01.001. View

15.

Liberti M, Locasale J . The Warburg Effect: How Does it Benefit Cancer Cells?. Trends Biochem Sci. 2016; 41(3):211-218. PMC: 4783224. DOI: 10.1016/j.tibs.2015.12.001. View

16.

Kornberg M, Bhargava P, Kim P, Putluri V, Snowman A, Putluri N . Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science. 2018; 360(6387):449-453. PMC: 5924419. DOI: 10.1126/science.aan4665. View

17.

Yang Y, Bedford M . Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2012; 13(1):37-50. DOI: 10.1038/nrc3409. View

18.

Yang M, Vousden K . Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016; 16(10):650-62. DOI: 10.1038/nrc.2016.81. View

19.

Shestov A, Liu X, Ser Z, Cluntun A, Hung Y, Huang L . Quantitative determinants of aerobic glycolysis identify flux through the enzyme GAPDH as a limiting step. Elife. 2014; 3. PMC: 4118620. DOI: 10.7554/eLife.03342. View

20.

Wang H, Hsieh Y, Cheng W, Lin C, Lin Y, Yang S . JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α-mediated glucose metabolism. Proc Natl Acad Sci U S A. 2013; 111(1):279-84. PMC: 3890888. DOI: 10.1073/pnas.1311249111. View