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

01-12-2022 | Gastric Cancer | Primary research

CARM1 promotes gastric cancer progression by regulating TFE3 mediated autophagy enhancement through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways

Authors: Suzhen Yang, Jing Zhang, Di Chen, Jiayi Cao, Ying Zheng, Yuying Han, Yirong Jin, Shuhui Wang, Ting Wang, Lin Ma, Tingting Luo, Yan Wang, Wen Qin, Lei Dong

Published in: Cancer Cell International | Issue 1/2022

Login to get access

Abstract

Background

The role of CARM1 in tumors is inconsistent. It acts as an oncogene in most cancers but it inhibits the progression of liver and pancreatic cancers. CARM1 has recently been reported to regulate autophagy, but this function is also context-dependent. However, the effect of CARM1 on gastric cancer (GC) has not been studied. We aimed to explore whether CARM1 was involved in the progression of GC by regulating autophagy.

Methods

The clinical values of CARM1 and autophagy in GC were evaluated by immunohistochemistry and qRT–PCR. Transmission electron microscopy, immunofluorescence and western blotting were employed to identify autophagy. The role of CARM1 in GC was investigated by CCK-8, colony formation and flow cytometry assays in vitro and a xenograft model in vivo. Immunoprecipitation assays were performed to determine the interaction of CARM1 and TFE3.

Results

CARM1 was upregulated in clinical GC tissues and cell lines, and higher CARM1 expression predicted worse prognosis. CARM1 enhanced GC cell proliferation, facilitated G1-S transition and inhibited ER stress-induced apoptosis by regulating autophagy. Importantly, treatment with a CARM1 inhibitor rescued the tumor-promoting effects of CARM1 both in vitro and in vivo. Furthermore, we demonstrated that CARM1 promoted TFE3 nuclear translocation to induce autophagy through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways.

Conclusion

CARM1 promoted GC cell proliferation, accelerated G1-S transition and reduced ER stress-induced apoptosis by regulating autophagy. Mechanistically, CARM1 triggered autophagy by facilitating TFE3 nuclear translocation through the AMPK-mTOR and AMPK-CARM1-TFE3 signaling pathways.
Appendix
Available only for authorised users
Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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):209–49.CrossRefPubMed
2.
Joshi SS, Badgwell BD. Current treatment and recent progress in gastric cancer. CA Cancer J Clin. 2021;71(3):264–79.PubMed
3.
Yang ZF, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol. 2010;22(2):124–31.PubMed
4.
5.
Altman JK, Szilard A, Goussetis DJ, Sassano A, Colamonici M, Gounaris E, et al. Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting. Clin Cancer Res. 2014;20(9):2400–9.PubMedPubMedCentral
6.
Kun Z, Hanqing G, Hailing T, Yuan Y, Jun Z, Lingxia Z, et al. Gastrin enhances autophagy and promotes gastric carcinoma proliferation via inducing AMPKα. Oncol Res. 2017;25(8):1399–407.PubMedPubMedCentral
7.
Masui A, Hamada M, Kameyama H, Wakabayashi K, Takasu A, Imai T, et al. Autophagy as a survival mechanism for squamous cell carcinoma cells in endonuclease G-mediated apoptosis. PLoS ONE. 2016;11(9):e0162786.PubMedPubMedCentral
8.
Wang Y, Xiong H, Liu D, Hill C, Ertay A, Li J, et al. Autophagy inhibition specifically promotes epithelial-mesenchymal transition and invasion in RAS-mutated cancer cells. Autophagy. 2019;15(5):886–99.PubMedPubMedCentral
9.
Onorati AV, Dyczynski M, Ojha R, Amaravadi RK. Targeting autophagy in cancer. Cancer. 2018;124(16):3307–18.PubMed
10.
Baek SH, Kim KI. Epigenetic control of autophagy: nuclear events gain more attention. Mol Cell. 2017;65(5):781–5.PubMed
11.
Suresh S, Huard S, Dubois T. CARM1/PRMT4: making its mark beyond its function as a transcriptional coactivator. Trends Cell Biol. 2021;31(5):402–17.PubMed
12.
13.
Kim JH, Yoo BC, Yang WS, Kim E, Hong S, Cho JY. The role of protein arginine methyltransferases in inflammatory responses. Mediators Inflamm. 2016;2016:4028353.PubMedPubMedCentral
14.
Al-Dhaheri M, Wu J, Skliris GP, Li J, Higashimato K, Wang Y, et al. CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res. 2011;71(6):2118–28.PubMedPubMedCentral
15.
Elakoum R, Gauchotte G, Oussalah A, Wissler MP, Clement-Duchene C, Vignaud JM, et al. CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie. 2014;97:210–8.PubMed
16.
Karakashev S, Zhu H, Wu S, Yokoyama Y, Bitler BG, Park PH, et al. CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun. 2018;9(1):631.PubMedPubMedCentral
17.
Majumder S, Liu Y, Ford OH 3rd, Mohler JL, Whang YE. Involvement of arginine methyltransferase CARM1 in androgen receptor function and prostate cancer cell viability. Prostate. 2006;66(12):1292–301.PubMed
18.
Ou CY, LaBonte MJ, Manegold PC, So AY, Ianculescu I, Gerke DS, et al. A coactivator role of CARM1 in the dysregulation of beta-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res. 2011;9(5):660–70.PubMedPubMedCentral
19.
Wang YP, Zhou W, Wang J, Huang X, Zuo Y, Wang TS, et al. Arginine methylation of MDH1 by CARM1 inhibits glutamine metabolism and suppresses pancreatic cancer. Mol Cell. 2016;64(4):673–87.PubMed
20.
Zhong XY, Yuan XM, Xu YY, Yin M, Yan WW, Zou SW, et al. CARM1 methylates GAPDH to regulate glucose metabolism and is suppressed in liver cancer. Cell Rep. 2018;24(12):3207–23.PubMed
21.
Drew AE, Moradei O, Jacques SL, Rioux N, Boriack-Sjodin AP, Allain C, et al. Identification of a CARM1 inhibitor with potent in vitro and in vivo activity in preclinical models of multiple myeloma. Sci Rep. 2017;7(1):17993.PubMedPubMedCentral
22.
Greenblatt SM, Man N, Hamard PJ, Asai T, Karl D, Martinez C, et al. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis. Cancer Cell. 2019;35(1):156.PubMed
23.
Li S, Cheng D, Zhu B, Yang Q. The overexpression of CARM1 promotes human osteosarcoma cell proliferation through the pGSK3beta/beta-catenin/cyclinD1 signaling pathway. Int J Biol Sci. 2017;13(8):976–84.PubMedPubMedCentral
24.
Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol. 2019;20(10):642–57.PubMed
25.
Jarrold J, Davies CC. PRMTs and arginine methylation: cancer’s best-kept secret? Trends Mol Med. 2019;25(11):993–1009.PubMed
26.
Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature. 2016;534(7608):553–7.PubMedPubMedCentral
27.
Liu Y, Wang T, Ji YJ, Johnson K, Liu H, Johnson K, et al. A C9orf72-CARM1 axis regulates lipid metabolism under glucose starvation-induced nutrient stress. Genes Dev. 2018;32(21–22):1380–97.PubMedPubMedCentral
28.
Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26(24):9220–31.PubMedPubMedCentral
29.
Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2(5):252–62.PubMed
30.
Hendershot LM, Valentine VA, Lee AS, Morris SW, Shapiro DN. Localization of the gene encoding human BiP/GRP78, the endoplasmic reticulum cognate of the HSP70 family, to chromosome 9q34. Genomics. 1994;20(2):281–4.PubMed
31.
Wang XJ, Yu J, Wong SH, Cheng AS, Chan FK, Ng SS, et al. A novel crosstalk between two major protein degradation systems: regulation of proteasomal activity by autophagy. Autophagy. 2013;9(10):1500–8.PubMed
32.
Pankiv S, Clausen TH, Lamark T, Brech A, Bruun JA, Outzen H, et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J Biol Chem. 2007;282(33):24131–45.PubMed
33.
McComb S, Chan PK, Guinot A, Hartmannsdottir H, Jenni S, Dobay MP, et al. Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7. Sci Adv. 2019;5(7):eaau9433.PubMedPubMedCentral
34.
Slade L, Pulinilkunnil T. The MiTF/TFE family of transcription factors: master regulators of organelle signaling, metabolism, and stress adaptation. Mol Cancer Res. 2017;15(12):1637–43.PubMed
35.
Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, et al. Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature. 2015;524(7565):361–5.PubMedPubMedCentral
36.
Rehli M, Lichanska A, Cassady AI, Ostrowski MC, Hume DA. TFEC is a macrophage-restricted member of the microphthalmia-TFE subfamily of basic helix-loop-helix leucine zipper transcription factors. J Immunol. 1999;162(3):1559–65.PubMed
37.
Martina JA, Puertollano R. TFEB and TFE3: the art of multi-tasking under stress conditions. Transcription. 2017;8(1):48–54.PubMed
38.
Abdulrahman RM, Boon MR, Sips HC, Guigas B, Rensen PC, Smit JW, et al. Impact of Metformin and compound C on NIS expression and iodine uptake in vitro and in vivo: a role for CRE in AMPK modulation of thyroid function. Thyroid. 2014;24(1):78–87.PubMed
39.
Bedford MT, Richard S. Arginine methylation an emerging regulator of protein function. Mol Cell. 2005;18(3):263–72.PubMed
40.
Hale AN, Ledbetter DJ, Gawriluk TR, Rucker EB 3rd. Autophagy: regulation and role in development. Autophagy. 2013;9(7):951–72.PubMedPubMedCentral
41.
Mathew R, Karp CM, Beaudoin B, Vuong N, Chen GH, Chen HY, et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137(6):1062–75.PubMedPubMedCentral
42.
43.
Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59(1):59–65.PubMed
44.
Yang C, Pan Y. Fluorouracil induces autophagy-related gastric carcinoma cell death through Beclin-1 upregulation by miR-30 suppression. Tumour Biol. 2015;37:15489.
45.
Cao Y, Luo Y, Zou J, Ouyang J, Cai Z, Zeng X, et al. Autophagy and its role in gastric cancer. Clin Chim Acta. 2019;489:10–20.PubMed
46.
Hetz C, Papa FR. The unfolded protein response and cell fate control. Mol Cell. 2018;69(2):169–81.PubMed
47.
Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014;25(5):563–73.PubMed
48.
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099–108.PubMed
49.
Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 1998;12(7):982–95.PubMedPubMedCentral
50.
Greenblatt SM, Man N, Hamard PJ, Asai T, Karl D, Martinez C, et al. CARM1 is essential for myeloid leukemogenesis but dispensable for normal hematopoiesis. Cancer Cell. 2018;33(6):1111-27.e5.PubMedPubMedCentral
51.
Veazey KJ, Cheng D, Lin K, Villarreal OD, Gao G, Perez-Oquendo M, et al. CARM1 inhibition reduces histone acetyltransferase activity causing synthetic lethality in CREBBP/EP300-mutated lymphomas. Leukemia. 2020;34(12):3269–85.PubMedPubMedCentral
52.
Rojas-Puentes LL, Gonzalez-Pinedo M, Crismatt A, Ortega-Gomez A, Gamboa-Vignolle C, Nuñez-Gomez R, et al. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat Oncol (London, England). 2013;8:209.
53.
Dong X, Wang Y, Zhou Y, Wen J, Wang S, Shen L. Aquaporin 3 facilitates chemoresistance in gastric cancer cells to cisplatin via autophagy. Cell Death Discovery. 2016;2:16087.PubMedPubMedCentral
54.
Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet. 2011;20(19):3852–66.PubMed
55.
Lim JA, Meena NK, Raben N. Pros and cons of different ways to address dysfunctional autophagy in Pompe disease. Ann Transl Med. 2019;7(13):279.PubMedPubMedCentral
56.
Thirupathi A, Chang YZ. Role of AMPK and its molecular intermediates in subjugating cancer survival mechanism. Life Sci. 2019;227:30–8.PubMed
57.
Kim YH, Liang H, Liu X, Lee JS, Cho JY, Cheong JH, et al. AMPKα modulation in cancer progression: multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. Cancer Res. 2012;72(10):2512–21.PubMed
58.
Shimobayashi M, Hall MN. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol. 2014;15(3):155–62.PubMed
59.
Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, et al. TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006;126(5):955–68.PubMed
60.
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 2008;30(2):214–26.PubMedPubMedCentral
61.
Stouth DW, vanLieshout TL, Ng SY, Webb EK, Manta A, Moll Z, et al. CARM1 regulates AMPK signaling in skeletal muscle. iScience. 2020;23(11):101755.PubMedPubMedCentral
Metadata
Title
CARM1 promotes gastric cancer progression by regulating TFE3 mediated autophagy enhancement through the cytoplasmic AMPK-mTOR and nuclear AMPK-CARM1-TFE3 signaling pathways
Authors
Suzhen Yang
Jing Zhang
Di Chen
Jiayi Cao
Ying Zheng
Yuying Han
Yirong Jin
Shuhui Wang
Ting Wang
Lin Ma
Tingting Luo
Yan Wang
Wen Qin
Lei Dong
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/s12935-022-02522-0

Other articles of this Issue 1/2022

Cancer Cell International 1/2022 Go to the issue

Research

The expression changes of transcription factors including ANKZF1, LEF1, CASZ1, and ATOH1 as a predictor of survival rate in colorectal cancer: a large-scale analysis

Research

Comprehensive analyses reveal the carcinogenic and immunological roles of ANLN in human cancers

Primary research

RPL15 promotes hepatocellular carcinoma progression via regulation of RPs-MDM2-p53 signaling pathway

Review

Modifying oncolytic virotherapy to overcome the barrier of the hypoxic tumor microenvironment. Where do we stand?

Review

Emerging role of circular RNAs in the pathogenesis of ovarian cancer

Review

Immune checkpoint inhibitor-related adverse cardiac events in patients with lung cancer: a systematic review and meta-analysis
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