Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer
Authors: Xingjun Guo
Shuo Yu
Xiaodong Xu
Chengjian Shi
Yan Zhao
Jun Gong
Hang Zhang
Chuan He
Feng Zhu
Renyi Qin
Ji Miao
Simiao Xu
Jianxin Jiang
Yu Xie
Rui Tian
Yechen Feng
Wenyi Wei
Jun Liu
Feng Peng
Ruizhi He
Jianpin Guo
Min Wang
Xu Li
Min Li
Journal: Molecular Cancer (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: METTL14; N6-methyladenosine; PERP; Pancreatic cancer; m6A.
Affiliations: Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China., Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA., Department of Trauma Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China., Department of Endocrinology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China., Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA., The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China., Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA., Department of Hepatic-Biliary-Pancreatic Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China., Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. ., Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA, 02215, USA. ., Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA. ., Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, Hubei, China. .

Abstract:  Background: Pancreatic cancer is one of the most lethal human cancers. N6-methyladenosine (m6A), 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 m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A 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 m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A 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 m6A-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 m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment. 

Retracted: No

PubPeer comments:
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 2014 correction has nothing to do with figure 2C. , 
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 #3 Viewing Figure 5 using Forensically illustrates some other possible areas of similarity, including in the background. Top: boxes showing areas of similarity; Bottom: without boxes, showing *possible* splice locations. *** ![file] *** ![file] , 
 2020 retraction. https: journals.plos.org plosone article?id=10.1371 journal.pone.0228994 Following the publication and correction of this article [1, 2], additional concerns have been raised regarding Fig 2 and Fig 5: In Fig 2C, lane 2 and 3 in the activated u03b2-catenin panel, representing the T3 and the T3-Wnt3a samples, appear similar. In Fig 2C, lane 1 and 3 in the Actin panel, representing the Ctrl and the T3-Wnt3a samples, appear similar. In Fig 2C, vertical discontinuities in background have been detected between lane 3 and lane 4 of the Activated u03b2-catenin panel, and between lane 1 and lane 2 in the Actin panel. In Fig 5, the T3- and T3+ results for the WB:TRu03b11 Inputs panel appear similar. In Fig 5, lanes 3, 4 (TRu03b11 IP) appear similar to lanes 5, 6 (u03b2-catenin IP) in the WB:u03b2-catenin panel. In Fig 5, the T3- and T3+ results for the WB:u03b2-catenin Inputs panel appear similar. In Fig 5, irregularities have been detected in background granulation just below the Inputs (+) band of the WB: u03b2-catenin panel. The authors have indicated that the underlying primary data for the figures above are no longer available. In light of the concerns affecting multiple figure panels that question the integrity of these data, the PLOS ONE Editors retract this article. MS, SS, INL, JN, DA did not respond. MP did not agree with retraction. References 1.Sirakov M, Skah S, Lone IN, Nadjar J, Angelov D, Plateroti M (2012) Multi-Level Interactions between the Nuclear Receptor TRu03b11 and the WNT Effectors u03b2-Catenin Tcf4 in the Intestinal Epithelium. PLoS ONE 7(4): e34162. https: doi.org 10.1371 journal.pone.0034162 pmid:22509275 2.The PLOS ONE Staff (2014) Correction: Multi-Level Interactions between the Nuclear Receptor TRu03b11 and the WNT Effectors u03b2-Catenin Tcf4 in the Intestinal Epithelium. PLoS ONE 9(3): e93418. https: doi.org 10.1371 journal.pone.0093418 ,