Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cancer Cell International
Published in: Cancer Cell International 1/2022

Open Access 01-12-2022 | Primary research

METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification

Authors: Yiming Xu, Dandan Lv, Chao Yan, Hua Su, Xue Zhang, Yangfeng Shi, Kejing Ying

Published in: Cancer Cell International | Issue 1/2022

Login to get access

Abstract

Background

N6-methyladenosine (m6A) has emerged as a significant regulator of the progress of various cancers. However, its role in lung adenocarcinoma (LUAD) remains unclear. Here, we explored the biological function and underlying mechanism of methyltransferase-like 3 (METTL3), the main catalyst of m6A, in LUAD progression.

Methods

The expression of m6A, METTL3, YTHDF1 and SLC7A11 were detected by immunochemistry or/and online datasets in LUAD patients. The effects of METTL3 on LUAD cell proliferation, apoptosis and ferroptosis were assessed through in vitro loss-and gain-of-function experiments. The in vivo effect on tumorigenesis of METTL3 was evaluated using the LUAD cell xenograft mouse model. MeRIP-seq, RNA immunoprecipitation and RNA stability assay were conducted to explore the molecular mechanism of METTL3 in LUAD.

Results

The results showed that the m6A level, as well as the methylase METTL3 were both significantly elevated in LUAD patients and lung cancer cells. Functionally, we found that METTL3 could promote proliferation and inhibit ferroptosis in different LUAD cell models, while METTL3 knockdown suppressed LUAD growth in cell-derived xenografts. Mechanistically, solute carrier 7A11 (SLC7A11), the subunit of system Xc−, was identified as the direct target of METTL3 by mRNA-seq and MeRIP-seq. METTL3-mediated m6A modification could stabilize SLC7A11 mRNA and promote its translation, thus promoting LUAD cell proliferation and inhibiting cell ferroptosis, a novel form of programmed cell death. Additionally, we demonstrated that YTHDF1, a m6A reader, was recruited by METTL3 to enhance SLC7A11 m6A modification. Moreover, the expression of YTHDF1 and SLC7A11 were positively correlated with METTL3 and m6A in LUAD tissues.

Conclusions

These findings reinforced the oncogenic role of METTL3 in LUAD progression and revealed its underlying correlation with cancer cell ferroptosis; these findings also indicate that METTL3 is a promising novel target in LUAD diagnosis and therapy.
Appendix
Available only for authorised users
Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.PubMed
2.
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021;149(4):778–89.
3.
Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.PubMed
4.
Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485(7397):201–6.PubMed
5.
Frye M, Harada BT, Behm M, He C. RNA modifications modulate gene expression during development. Science. 2018;361(6409):1346–9.PubMedPubMedCentral
6.
Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014;16(2):191–8.PubMedPubMedCentral
7.
Zhang H, Shi X, Huang T, Zhao X, Chen W, Gu N, Zhang R. Dynamic landscape and evolution of m6A methylation in human. Nucleic Acids Res. 2020;48(11):6251–64.PubMedPubMedCentral
8.
Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169(7):1187–200.PubMedPubMedCentral
9.
Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37(3):270–88.PubMedPubMedCentral
10.
Deng X, Su R, Weng H, Huang H, Li Z, Chen J. RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res. 2018;28(5):507–17.PubMedPubMedCentral
11.
Wang T, Kong S, Tao M, Ju S. The potential role of RNA N6-methyladenosine in cancer progression. Mol Cancer. 2020;19(1):88–88.PubMedPubMedCentral
12.
Wanna-udom S, Terashima M, Lyu H, Ishimura A, Takino T, Sakari M, Tsukahara T, Suzuki T. The m6A methyltransferase METTL3 contributes to transforming growth factor-beta-induced epithelial-mesenchymal transition of lung cancer cells through the regulation of JUNB. Biochem Biophys Res Commun. 2020;524(1):150–5.PubMed
13.
Sheng H, Li Z, Su S, Sun W, Zhang X, Li L, Li J, Liu S, Lu B, Zhang S, Shan C. YTH domain family 2 promotes lung cancer cell growth by facilitating 6-phosphogluconate dehydrogenase mRNA translation. Carcinogenesis. 2020;41(5):541–50.PubMed
14.
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–72.PubMedPubMedCentral
15.
Li J, Cao F, Yin H-L, Huang Z-J, Lin Z-T, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88–88.PubMedPubMedCentral
16.
Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv Mater. 2019;31(51):1904197.
17.
Mou Y, Wang J, Wu J, He D, Zhang C, Duan C, Li B. Ferroptosis, a new form of cell death: opportunities and challenges in cancer. J Hematol Oncol. 2019;12(1):34–34.PubMedPubMedCentral
18.
Liu P, Wu D, Duan J, Xiao H, Zhou Y, Zhao L, Feng Y. NRF2 regulates the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via FOCAD-FAK signaling pathway. Redox Biol. 2020;37: 101702.PubMedPubMedCentral
19.
Chen P, Wu Q, Feng J, Yan L, Sun Y, Liu S, Xiang Y, Zhang M, Pan T, Chen X, Duan T, Zhai L, Zhai B, Wang W, Zhang R, Chen B, Han X, Li Y, Chen L, Liu Y, Huang X, Jin T, Zhang W, Luo H, Chen X, Li Y, Li Q, Li G, Zhang Q, Zhuo L, Yang Z, Tang H, Xie T, Ouyang X, Sui X. Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther. 2020;5(1):51.PubMedPubMedCentral
20.
Ye J, Wang Z, Chen X, Jiang X, Dong Z, Hu S, Li W, Liu Y, Liao B, Han W, Shen J, Xiao M. YTHDF1-enhanced iron metabolism depends on TFRC m(6)A methylation. Theranostics. 2020;10(26):12072–89.PubMedPubMedCentral
21.
Song Z, Jia G, Ma P, Cang S. Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis. Life Sci. 2021;276: 119399.PubMed
22.
Jin W, Xu H-X, Zhang S-R, Li H, Wang W-Q, Gao H-L, Wu C-T, Xu J-Z, Qi Z-H, Li S, Ni Q-X, Liu L, Yu X-J. Tumor-infiltrating NETs predict postsurgical survival in patients with pancreatic ductal adenocarcinoma. Ann Surg Oncol. 2019;26(2):635–43.PubMed
23.
Shen C, Xuan B, Yan T, Ma Y, Xu P, Tian X, Zhang X, Cao Y, Ma D, Zhu X, Zhang Y, Fang J-Y, Chen H, Hong J. m(6)A-dependent glycolysis enhances colorectal cancer progression. Mol Cancer. 2020;19(1):72–72.PubMedPubMedCentral
24.
Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK, Varambally S. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649–58.PubMedPubMedCentral
25.
26.
Shi R, Ying S, Li Y, Zhu L, Wang X, Jin H. Linking the YTH domain to cancer: the importance of YTH family proteins in epigenetics. Cell Death Dis. 2021;12(4):346–346.PubMedPubMedCentral
27.
Wang Q, Guo X, Li L, Gao Z, Su X, Ji M, Liu J. N(6)-methyladenosine METTL3 promotes cervical cancer tumorigenesis and Warburg effect through YTHDF1/HK2 modification. Cell Death Dis. 2020;11(10):911–911.PubMedPubMedCentral
28.
Zhao W, Cui Y, Liu L, Ma X, Qi X, Wang Y, Liu Z, Ma S, Liu J, Wu J. METTL3 facilitates oral squamous cell carcinoma tumorigenesis by enhancing c-Myc stability via YTHDF1-mediated m(6)A modification. Mol Ther Nucleic Acids. 2020;20:1–12.PubMedPubMedCentral
29.
Duruisseaux M, Esteller M. Lung cancer epigenetics: from knowledge to applications. Semin Cancer Biol. 2018;51:116–28.PubMed
30.
Bennett RL, Licht JD. Targeting epigenetics in cancer. Annu Rev Pharmacol Toxicol. 2018;58:187–207.PubMed
31.
Masaldan S, Bush AI, Devos D, Rolland AS, Moreau C. Striking while the iron is hot: iron metabolism and ferroptosis in neurodegeneration. Free Radic Biol Med. 2019;133:221–33.PubMed
32.
Zhang Z, Guo M, Li Y, Shen M, Kong D, Shao J, Ding H, Tan S, Chen A, Zhang F, Zheng S. RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2020;16(8):1482–505.PubMed
33.
Li Y, Cao Y, Xiao J, Shang J, Tan Q, Ping F, Huang W, Wu F, Zhang H, Zhang X. Inhibitor of apoptosis-stimulating protein of p53 inhibits ferroptosis and alleviates intestinal ischemia/reperfusion-induced acute lung injury. Cell Death Differ. 2020;27(9):2635–50.PubMedPubMedCentral
34.
Li Y, Feng D, Wang Z, Zhao Y, Sun R, Tian D, Liu D, Zhang F, Ning S, Yao J, Tian X. Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ. 2019;26(11):2284–99.PubMedPubMedCentral
35.
Su L, Jiang X, Yang C, Zhang J, Chen B, Li Y, Yao S, Xie Q, Gomez H, Murugan R, Peng Z. Pannexin 1 mediates ferroptosis that contributes to renal ischemia/reperfusion injury. J Biol Chem. 2019;294(50):19395–404.PubMedPubMedCentral
36.
Zeng C, Huang W, Li Y, Weng H. Roles of METTL3 in cancer: mechanisms and therapeutic targeting. J Hematol Oncol. 2020;13(1):117–117.PubMedPubMedCentral
37.
Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M, Klimek VM, Garrett-Bakelman FE, Melnick A, Carroll M, Mason CE, Jaffrey SR, Kharas MG. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23(11):1369–76.PubMedPubMedCentral
38.
Jia R, Chai P, Wang S, Sun B, Xu Y, Yang Y, Ge S, Jia R, Yang Y-G, Fan X. m(6)A modification suppresses ocular melanoma through modulating HINT2 mRNA translation. Mol Cancer. 2019;18(1):161–161.PubMedPubMedCentral
39.
Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)A methyltransferase METTL3 promotes translation in human cancer cells. Mol Cell. 2016;62(3):335–45.PubMedPubMedCentral
40.
Ma L, Chen T, Zhang X, Miao Y, Tian X, Yu K, Xu X, Niu Y, Guo S, Zhang C, Qiu S, Qiao Y, Fang W, Du L, Yu Y, Wang J. The m(6)A reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 2021;38: 101801.PubMed
41.
Lin W, Wang C, Liu G, Bi C, Wang X, Zhou Q, Jin H. SLC7A11/xCT in cancer: biological functions and therapeutic implications. Am J Cancer Res. 2020;10(10):3106–26.PubMedPubMedCentral
42.
Hu K, Li K, Lv J, Feng J, Chen J, Wu H, Cheng F, Jiang W, Wang J, Pei H, Chiao PJ, Cai Z, Chen Y, Liu M, Pang X. Suppression of the SLC7A11/glutathione axis causes synthetic lethality in KRAS-mutant lung adenocarcinoma. J Clin Invest. 2020;130(4):1752–66.PubMedPubMedCentral
43.
Lim JKM, Delaidelli A, Minaker SW, Zhang H-F, Colovic M, Yang H, Negri GL, von Karstedt S, Lockwood WW, Schaffer P, Leprivier G, Sorensen PH. Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc Natl Acad Sci U S A. 2019;116(19):9433–42.PubMedPubMedCentral
44.
Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, Fulda S, Gascón S, Hatzios SK, Kagan VE, Noel K, Jiang X, Linkermann A, Murphy ME, Overholtzer M, Oyagi A, Pagnussat GC, Park J, Ran Q, Rosenfeld CS, Salnikow K, Tang D, Torti FM, Torti SV, Toyokuni S, Woerpel KA, Zhang DD. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.PubMedPubMedCentral
45.
Miotto G, Rossetto M, Di Paolo ML, Orian L, Venerando R, Roveri A, Vučković A-M, BoselloTravain V, Zaccarin M, Zennaro L, Maiorino M, Toppo S, Ursini F, Cozza G. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol. 2020;28:101328–101328.PubMed
46.
Zhao Y, Shi Y, Shen H, Xie W. m(6)A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020;13(1):35–35.PubMedPubMedCentral
47.
Lin X, Chai G, Wu Y, Li J, Chen F, Liu J, Luo G, Tauler J, Du J, Lin S, He C, Wang H. RNA m(6)A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail. Nat Commun. 2019;10(1):2065–2065.PubMedPubMedCentral
Metadata
Title
METTL3 promotes lung adenocarcinoma tumor growth and inhibits ferroptosis by stabilizing SLC7A11 m6A modification
Authors
Yiming Xu
Dandan Lv
Chao Yan
Hua Su
Xue Zhang
Yangfeng Shi
Kejing Ying
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2022
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-021-02433-6

Other articles of this Issue 1/2022

Cancer Cell International 1/2022 Go to the issue

Review

Landmarks in pancreatic cancer studies

Research

Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer

Review

Current understanding of epigenetics role in melanoma treatment and resistance

Research

Establishment and characterization of a new intrahepatic cholangiocarcinoma cell line derived from a Chinese patient

Research

Crosstalk between tumor-associated macrophages and tumor cells promotes chemoresistance via CXCL5/PI3K/AKT/mTOR pathway in gastric cancer

Primary research

SGLT2 inhibition restrains thyroid cancer growth via G1/S phase transition arrest and apoptosis mediated by DNA damage response signaling pathways
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits