Upregulation of METTL14 Mediates the Elevation of PERP MRNA N Adenosine Methylation Promoting the Growth and Metastasis of Pancreatic Cancer

Overview

Journal Mol Cancer

Publisher Biomed Central

Specialties Molecular Biology
Oncology

Date 2020 Aug 27

PMID 32843065

Citations 139

Authors

Min Wang

Jun Liu

Yan Zhao

Ruizhi He

Xiaodong Xu

Xingjun Guo

Xu Li

Simiao Xu

Ji Miao

Jianpin Guo

Hang Zhang

Jun Gong

Feng Zhu

Rui Tian

Chengjian Shi

Feng Peng

Yechen Feng

Shuo Yu

Yu Xie

Jianxin Jiang

Min Li

Wenyi Wei

Chuan He

Renyi Qin

Affiliations

Soon will be listed here.

Abstract

Background: Pancreatic cancer is one of the most lethal human cancers. N-methyladenosine (mA), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive.

Methods: LC/MS was used to profile mA levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of mA regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14.

Results: We found that the mA levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates mA methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an mA-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells.

Conclusions: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via mA modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

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References

Li A, Chen Y, Ping X, Yang X, Xiao W, Yang Y . Cytoplasmic mA reader YTHDF3 promotes mRNA translation. Cell Res. 2017; 27(3):444-447. PMC: 5339832. DOI: 10.1038/cr.2017.10. View

Tong J, Flavell R, Li H . RNA mA modification and its function in diseases. Front Med. 2018; 12(4):481-489. DOI: 10.1007/s11684-018-0654-8. View

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Wang X, Zhao B, Roundtree I, Lu Z, Han D, Ma H . N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015; 161(6):1388-99. PMC: 4825696. DOI: 10.1016/j.cell.2015.05.014. View

Guo X, Zheng L, Jiang J, Zhao Y, Wang X, Shen M . Blocking NF-κB Is Essential for the Immunotherapeutic Effect of Recombinant IL18 in Pancreatic Cancer. Clin Cancer Res. 2016; 22(23):5939-5950. DOI: 10.1158/1078-0432.CCR-15-1144. View

Meng J, Lu Z, Liu H, Zhang L, Zhang S, Chen Y . A protocol for RNA methylation differential analysis with MeRIP-Seq data and exomePeak R/Bioconductor package. Methods. 2014; 69(3):274-81. PMC: 4194139. DOI: 10.1016/j.ymeth.2014.06.008. View

Xiao W, Adhikari S, Dahal U, Chen Y, Hao Y, Sun B . Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell. 2016; 61(4):507-519. DOI: 10.1016/j.molcel.2016.01.012. View

Wang S, Chai P, Jia R, Jia R . Novel insights on mA RNA methylation in tumorigenesis: a double-edged sword. Mol Cancer. 2018; 17(1):101. PMC: 6054842. DOI: 10.1186/s12943-018-0847-4. View

Li Z, Chen B, Dong W, Xu W, Song M, Fang M . Epigenetic activation of PERP transcription by MKL1 contributes to ROS-induced apoptosis in skeletal muscle cells. Biochim Biophys Acta Gene Regul Mech. 2018; . DOI: 10.1016/j.bbagrm.2018.07.011. View

10.

. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017; 32(2):185-203.e13. PMC: 5964983. DOI: 10.1016/j.ccell.2017.07.007. View

11.

Xia T, Wu X, Cao M, Zhang P, Shi G, Zhang J . The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion. Pathol Res Pract. 2019; 215(11):152666. DOI: 10.1016/j.prp.2019.152666. View

12.

Wang X, Lu Z, Gomez A, Hon G, Yue Y, Han D . N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2013; 505(7481):117-20. PMC: 3877715. DOI: 10.1038/nature12730. View

13.

Attardi L, Reczek E, Cosmas C, Demicco E, McCurrach M, Lowe S . PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 2000; 14(6):704-18. PMC: 316461. View

14.

Patil D, Pickering B, Jaffrey S . Reading mA in the Transcriptome: mA-Binding Proteins. Trends Cell Biol. 2017; 28(2):113-127. PMC: 5794650. DOI: 10.1016/j.tcb.2017.10.001. View

15.

Beaudry V, Jiang D, Dusek R, Park E, Knezevich S, Ridd K . Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis. PLoS Genet. 2010; 6(10):e1001168. PMC: 2958815. DOI: 10.1371/journal.pgen.1001168. View

16.

Davies L, Spiller D, White M, Grierson I, Paraoan L . PERP expression stabilizes active p53 via modulation of p53-MDM2 interaction in uveal melanoma cells. Cell Death Dis. 2011; 2:e136. PMC: 3101815. DOI: 10.1038/cddis.2011.19. View

17.

Middleton G, Palmer D, Greenhalf W, Ghaneh P, Jackson R, Cox T . Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. Lancet Oncol. 2017; 18(4):486-499. DOI: 10.1016/S1470-2045(17)30084-0. View

18.

Vu L, Pickering B, Cheng Y, Zaccara S, Nguyen D, Minuesa G . The N-methyladenosine (mA)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017; 23(11):1369-1376. PMC: 5677536. DOI: 10.1038/nm.4416. View

19.

Zhao B, Roundtree I, He C . Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2016; 18(1):31-42. PMC: 5167638. DOI: 10.1038/nrm.2016.132. View

20.

Ping X, Sun B, Wang L, Xiao W, Yang X, Wang W . Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014; 24(2):177-89. PMC: 3915904. DOI: 10.1038/cr.2014.3. View