[en] N6-methyladenosine (m6A) is the most prevalent RNA epigenetic regulator in cancer. However, the understanding of m6A modification on lipid metabolism regulation in colorectal cancer (CRC) is very limited. Here, we observed that human CRCs exhibited increased m6A mRNA methylation mediated by dysregulation of m6A erasers and readers. By performing methylated RNA-immunoprecipitation sequencing (MeRIP-seq) and transcriptomic sequencing (RNA-seq), we identified DEGS2 as a downstream target of m6A dysregulation. Overexpression or knockdown of DEGS2 confirmed the role of DEGS2 in proliferation, invasion and metastasis of CRC both in vitro and in vivo. Mechanistic studies identified the specific m6A modification site within DEGS2 mRNA, and mutation of this target site was found to drastically enhance the proliferative and invasive ability of CRC cells in vitro and promote tumorigenicity in vivo. Lipidome analysis showed that lipid metabolism was dysregulated in CRC. Moreover, ceramide synthesis was suppressed due to DEGS2 upregulation mediated by m6A modification in CRC tissues. Our findings highlight that the function of DEGS2 m6A methylation in CRC and extend the understanding of the importance of RNA epigenetics in cancer biology.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Guo, Wei ; Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Zhang, Cuiyu; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Feng, Panpan; Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Li, Mingying; Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Wang, Xia; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Xia, Yuan; Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
Li, Jingxin ; Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China. ljingxin@sdu.edu.cn
Language :
English
Title :
M6A methylation of DEGS2, a key ceramide-synthesizing enzyme, is involved in colorectal cancer progression through ceramide synthesis.
NSCF - National Natural Science Foundation of China [CN]
Funding text :
This work was supported in part by the National Natural Science Foundation of China (82000779, 31971061); and Taishan Pandeng Scholar Program of Shandong Province (tspd20210321).
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-Cancer J Clin. 2018;68:394–424. DOI: 10.3322/caac.21492
Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015 a systematic analysis for the Global Burden of Disease Study. JAMA Oncol. 2017;3:524–48. DOI: 10.1001/jamaoncol.2017.1747
Zhao BXS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42. DOI: 10.1038/nrm.2016.132
Meyer KD, Jaffrey SR. The dynamic epitranscriptome: N-6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014;15(5):313–26. DOI: 10.1038/nrm3785
Tong J, Flavell RA, Li H-B. RNA m6A modification and its function in diseases. Front Med. 2018;12:481–9. DOI: 10.1007/s11684-018-0654-8
Li ZJ, Weng HY, Su R, Weng XC, Zuo ZX, Li CY, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N-6-methyladenosine RNA demethylase. Cancer Cell. 2017;31:127–41. DOI: 10.1016/j.ccell.2016.11.017
Zhang SC, Zhao BS, Zhou AD, Lin KY, Zheng SP, Lu ZK, et al. m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31:591–606.e6. DOI: 10.1016/j.ccell.2017.02.013
Cai XL, Wang X, Cao C, Gao YE, Zhang SQ, Yang Z, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018;415:11–9. DOI: 10.1016/j.canlet.2017.11.018
Liu J, Eckert MA, Harada BT, Liu S-M, Lu Z, Yu K, et al. m6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer. Nat Cell Biol. 2018;20:1074–83. DOI: 10.1038/s41556-018-0174-4
Li T, Hu PS, Zuo ZX, Lin JF, Li XY, Wu QN, et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019;18:112. DOI: 10.1186/s12943-019-1038-7
Yang X, Zhang S, He CY, Xue P, Zhang LY, He ZR, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020;19:46. DOI: 10.1186/s12943-020-1146-4
Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Bio. 2008;9(2):139–150. DOI: 10.1038/nrm2329
Dressler KA, Mathias S, Kolesnick RN. Tumor-necrosis-factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science. 1992;255:1715–8. DOI: 10.1126/science.1313189
Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004;4:604–16. DOI: 10.1038/nrc1411
Casasampere M, Ordonez YF, Pou A, Casas J. Inhibitors of dihydroceramide desaturase 1: therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology. Chem Phys Lipids. 2016;197:33–44. DOI: 10.1016/j.chemphyslip.2015.07.025
Engel M, Chen A. The emerging role of mRNA methylation in normal and pathological behavior. Genes Brain Behav. 2018;17:e12428. DOI: 10.1111/gbb.12428
Lan Q, Liu PY, Haase J, Bell JL, Hüttelmaier S, Liu T. The critical role of rna m6a methylation in cancer. Cancer Res. 2019;79:1285–92. DOI: 10.1158/0008-5472.CAN-18-2965
Tuncel G, Kalkan R. Importance of m N-6-methyladenosine (m(6)A) RNA modification in cancer. Med Oncol.2019;36:36. DOI: 10.1007/s12032-019-1260-6
Yang Y, Shen F, Huang W, Qin S, Huang J-T, Sergi C. et al. Glucose is involved in the dynamic regulation of m6a in patients with type 2 diabetes. J Clin Endocrinol Metab. 2019;104:665–73. DOI: 10.1210/jc.2018-00619
Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V, et al. Essential role of METTL3-mediated m6A modification in glioma stem-like cells maintenance and radioresistance. Oncogene. 2018;37:522–33. DOI: 10.1038/onc.2017.351
Mathiyalagan P, Adamiak M, Mayourian J, Sassi Y, Liang YX, Agarwal N, et al. FTO-dependent N-6-methyladenosine regulates cardiac function during remodeling and repair. Circulation. 2019;139:518–32. DOI: 10.1161/CIRCULATIONAHA.118.033794
Dang W, Xie Y, Cao PF, Xin SY, Wang J, Li S, et al. N-6-methyladenosine and viral infection. Front Microbiol. 2019;10:417. DOI: 10.3389/fmicb.2019.00417
Meyer KD, Jaffrey SR. Rethinking m(6)A readers, writers, and erasers. Annu Rev Cell Dev Biol. 2017;33:319–42. DOI: 10.1146/annurev-cellbio-100616-060758
Fabrias G, Munoz-Olaya J, Cingolani F, Signorelli P, Casas J, Gagliostro V, et al. Dihydroceramide desaturase and dihydrosphingolipids: debutant players in the sphingolipid arena. Prog Lipid Res. 2012;51:82–94. DOI: 10.1016/j.plipres.2011.12.002
Selzner M, Bielawska A, Morse MA, Rudiger HA, Sindram D, Hannun YA, et al. Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer. Cancer Res. 2001;61:1233–40.
Gao X, Pang J, Li LY, Liu WP, Di JM, Sun QP, et al. Expression profiling identifies new function of collapsin response mediator protein 4 as a metastasis-suppressor in prostate cancer. Oncogene. 2010;29:4555–66. DOI: 10.1038/onc.2010.213
Yang Y, Jiang Y, Xie D, Liu M, Song N, Zhu JJ, et al. Inhibition of cell-adhesion protein DPYSL3 promotes metastasis of lung cancer. Resp Res. 2018;19:41. DOI: 10.1186/s12931-018-0740-0
Ma JZ, Yang F, Zhou CC, Liu F, Yuan JH, Wang F, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N-6-methyladenosine- dependent primary MicroRNA processing. Hepatology. 2017;65:529–43. DOI: 10.1002/hep.28885
Zhang CZ, Samanta D, Lu HQ, Bullen JW, Zhang HM, Chen I, et al. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m(6)A-demethylation of NANOG mRNA. Proc Natl Acad Sci USA. 2016;113:E2047–56. DOI: 10.1073/pnas.1602883113
Hua WF, Zhao Y, Jin XH, Yu DY, He J, Xie D, et al. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. Gynecol Oncol. 2018;151:356–65. DOI: 10.1016/j.ygyno.2018.09.015
Antony J, Tan TZ, Kelly Z, Low J, Choolani M, Recchi C, et al. The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer. Sci Signal. 2016;9:448–ra97. DOI: 10.1126/scisignal.aaf8175
Xu JH, Chen QK, Tian KY, Liang RR, Chen T, Gong AY, et al. m(6)A methyltransferase METTL3 maintains colon cancer tumorigenicity by suppressing SOCS2 to promote cell proliferation. Oncol Rep. 2020;44(3):973–6. DOI: 10.3892/or.2020.7665
Chen HR, Gao SS, Liu WX, Wong CC, Wu JF, Wu JT, et al. RNA N-6-methyladenosine methyltransferase METTL3 facilitates colorectal cancer by activating the m(6)A-GLUT1-mTORC1 axis and is a therapeutic target. Gastroenterology. 2021;160:1284–300.e16. DOI: 10.1053/j.gastro.2020.11.013
Shen CQ, Xuan BQ, Yan TT, Ma YR, Xu PP, Tian XL, et al. m(6)A-dependent glycolysis enhances colorectal cancer progression. Mol Cancer. 2020;19:72. DOI: 10.1186/s12943-020-01190-w
Garborg K, Holme O, Loberg M, Kalager M, Adami HO, Bretthauer M. Current status of screening for colorectal cancer. Ann Oncol. 2013;24:1963–72. DOI: 10.1093/annonc/mdt157
Siegel R, DeSantis C, Jemal A. Colorectal cancer statistics, 2014. Ca-Cancer J Clin. 2014;64:104–17. DOI: 10.3322/caac.21220
Edwards BK, Ward E, Kohler BA, Eheman C, Zauber AG, Anderson RN, et al. Annual Report to the Nation on the Status of Cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer. 2010;116(3):544–73. DOI: 10.1002/cncr.24760
Sargent D, Sobrero A, Grothey A, O’Connell MJ, Buyse M, Andre T, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27:872–7. DOI: 10.1200/JCO.2008.19.5362
Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen RL, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51:202–6. DOI: 10.1038/s41588-018-0312-8
Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30(1):44–56. DOI: 10.1093/annonc/mdy495
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4. DOI: 10.1126/science.1129139
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. DOI: 10.1126/science.aan6733
