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      m 6A mRNA methylation regulates AKT activity to promote the proliferation and tumorigenicity of endometrial cancer

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          Abstract

          N 6-methyladenosine (m 6A) mRNA methylation is a gene regulatory mechanism affecting cell differentiation and proliferation in development and cancer. To study the roles of m 6A mRNA methylation in cell proliferation and tumorigenicity, we investigated human endometrial cancer in which a hotspot R298P mutation is present in a key component of the methyltransferase complex (METTL14). We found ~70% of endometrial tumors exhibit reductions in m 6A methylation that are likely due to either this METTL14 mutation or reduced expression of METTL3, another component of the methyltransferase complex. These changes lead to increased proliferation and tumorigenicity of endometrial cancer cells through activation of the AKT pathway. Reductions in m 6A methylation lead to decreased expression of the negative AKT regulator PHLPP2 and increased expression of the positive AKT regulator mTORC2. Together, these results reveal reduced m 6A mRNA methylation as an oncogenic mechanism in endometrial cancer and identify m 6A methylation as a regulator of AKT signaling.

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          Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

          (2017)
          We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.
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            Cytoplasmic m6A reader YTHDF3 promotes mRNA translation

            Ang Li, Yu-Sheng Chen, Xiao-Li Ping … (2017)
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              TORC-specific phosphorylation of mammalian target of rapamycin (mTOR): phospho-Ser2481 is a marker for intact mTOR signaling complex 2.

              Jeremy Copp, Gerard Manning, Tony Hunter (2009)
              The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic component of two evolutionarily conserved signaling complexes. mTOR signaling complex 1 (mTORC1) is a key regulator of growth factor and nutrient signaling. S6 kinase is the best-characterized downstream effector of mTORC1. mTOR signaling complex 2 (mTORC2) has a role in regulating the actin cytoskeleton and activating Akt through S473 phosphorylation. Herein, we show that mTOR is phosphorylated differentially when associated with mTORC1 and mTORC2 and that intact complexes are required for these mTORC-specific mTOR phosphorylations. Specifically, we find that mTORC1 contains mTOR phosphorylated predominantly on S2448, whereas mTORC2 contains mTOR phosphorylated predominantly on S2481. Using S2481 phosphorylation as a marker for mTORC2 sensitivity to rapamycin, we find that mTORC2 formation is in fact rapamycin sensitive in several cancer cell lines in which it had been previously reported that mTORC2 assembly and function were rapamycin insensitive. Thus, phospho-S2481 on mTOR serves as a biomarker for intact mTORC2 and its sensitivity to rapamycin.
              Article 0 comments Cited 146 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100890575
                Journal ID (pubmed-jr-id): 21417
                Journal ID (nlm-ta): Nat Cell Biol
                Journal ID (iso-abbrev): Nat. Cell Biol.
                Title: Nature cell biology
                ISSN (Print): 1465-7392
                ISSN (Electronic): 1476-4679
                Publication date Nihms-submitted: 20 August 2018
                Publication date (Electronic): 27 August 2018
                Publication date (Print): September 2018
                Publication date PMC-release: 27 February 2019
                Volume: 20
                Issue: 9
                Pages: 1074-1083
                Affiliations
                [1 ]Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA.
                [2 ]Howard Hughes Medical Institute, Chicago, IL 60637, USA.
                [3 ]Department of Obstetrics and Gynecology/Section of Gynecologic Oncology, The University of Chicago, Chicago, IL 60637, USA.
                [4 ]Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
                [5 ]College of Chemistry, Sichuan University, Chengdu, 610065, China.
                [6 ]Committee on Cancer Biology and Medical Scientist Training Program, The University of Chicago, Chicago, IL 60637, USA.
                [7 ]Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
                [8 ]Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
                [9 ]Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
                [10 ]MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China.
                [11 ]Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
                Author notes

                AUTHOR CONTRIBUTIONS

                Jun L., M.A.E., B.T.H., E.L. and C.H. designed the experiments. M.A.E., S.M.T., S.L., Y.Y., J.H., S.C., Z.X, X.L, X.Y., and E.L. collected the patient samples with assistance from J.C., Z.Z., and Jz.L. Jun L., M.A.E., and B.T.H. performed the experiments with help from K.Y., S.M.T., A.C., and A.C.Z. Jun L., M.A.E., B.T.H., E.L. and C.H. analyzed the data and interpreted the findings. Z.L. aided with analysis of the sequencing data. Jz.L aided in the early design of experiments. Jun L. and B.T.H. wrote the manuscript with input from M.A.E., E.L., and C.H.

                [* ]Corresponding author. chuanhe@ 123456uchicago.edu (C.H.); elengyel@ 123456uchicago.edu (E.L)
                Article
                Manuscript ID: NIHMS1500485
                DOI: 10.1038/s41556-018-0174-4
                PMC ID: 6245953
                PubMed ID: 30154548
                SO-VID: c8965266-7fcd-48be-93b5-c71541b8abd2
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                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                ScienceOpen disciplines: Cell biology
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                ScienceOpen disciplines: Cell biology

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