|Table of Contents|

Research progress on ALKBH5 and its role in the occurrence and development of tumors

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2024 20
Page:
3999-4004
Research Field:
Publishing date:

Info

Title:
Research progress on ALKBH5 and its role in the occurrence and development of tumors
Author(s):
YIN Feng12SHI Zhenyu3TANG Yuying2WANG Yuting2LIU Hui2TAN Jing2DING Hao2CHEN Wengang1CHENG Feng1
1Department of Pharmacy,the Second Affiliated Hospital of Wannan Medical College,Anhui Wuhu 241000,China;2 School of Clinical Medicine,Wannan Medical College,Anhui Wuhu 241002,China;3School of Clinical Medicine,Anhui Medical University,Anhui Hefei 230031,China.
Keywords:
ALKBH5m6Atumor
PACS:
R730.231
DOI:
10.3969/j.issn.1672-4992.2024.20.035
Abstract:
AlkB homolog 5 (ALKBH5) is a m6A demethyltransferase protein,which removes the methylation of the nitrogen atom at the 6th position of adenine (A) on RNA.With the development of science and technology,more and more studies showed that ALKBH5 mediated m6A demethylation plays an important role in the tumorigenesis and development.This review focuses on the structure of ALKBH5,its role as an oncogene and tumor suppressor gene in tumorigenesis and development,and the regulation of ALKBH5 expression and function.The aim of this study is to provide new research ideas and therapeutic targets for m6A modification in basic and clinical medicine.

References:

[1] BOCCALETTO P,MACHNICKA MA,PURTA E,et al.MODOMICS:a database of RNA modification pathways.2017 update[J].Nucleic Acids Research,2018,46(D1):D303-D307.
[2] LIU J,YUE Y,HAN D,et al.A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation[J].Nature Chemical Biology,2014,10(2):93-95.
[3] PING XL,SUN BF,WANG L,et al.Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase[J].Cell Research,2014,24(2):177-189.
[4] CHOE J,LIN S,ZHANG W,et al.mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis[J].Nature,2018,561(7724):556-560.
[5] JIA G,FU Y,ZHAO X,et al.N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO[J].Nature Chemical Biology,2011,7(12):885-887.
[6] ZHENG G,DAHL JA,NIU Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J].Molecular Cell,2013,49(1):18-29.
[7] ALARCON CR,GOODARZI H,LEE H,et al.HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events[J].Cell,2015,162(6):1299-1308.
[8] ROUNDTREE IA,LUO GZ,ZHANG Z,et al.YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs[J].Elife,2017,6:e31311.
[9] DU H,ZHAO Y,HE J,et al.YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex[J].Nature Communication,2016,7:12626.
[10] SHI H,WANG X,LU Z,et al.YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA[J].Cell Research,2017,27(3):315-328.
[11] MEYER KD,PATIL DP,ZHOU J,et al.5' UTR m(6)A promotes cap-independent translation[J].Cell,2015,163(4):999-1010.
[12] TREWICK SC,HENSHAW TF,HAUSINGER RP,et al.Oxidative demethylation by Escherichia coli AlkB directly reverts DNA base damage[J].Nature,2002,419(6903):174-178.
[13] GERKEN T,GIRARD CA,TUNG YC,et al.The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase[J].Science,2007,318(5855):1469-1472.
[14] WEI J,LIU F,LU Z,et al.Differential m6A,m6Am,and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm[J].Molecular Cell,2018,71(6):973-985.e5.
[15] JIA G,YANG CG,YANG S,et al.Oxidative demethylation of 3-methylthymine and 3-methyluracil in single-stranded DNA and RNA by mouse and human FTO[J].FEBS Letters,2008,582(23-24):3313-3319.
[16] ZHENG G,DAHL JA,NIU Y,et al.ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility[J].Molecular Cell,2013,49(1):18-29.
[17] FU Y,DOMINISSINI D,RECHAVI G,et al.Gene expression regulation mediated through reversible m6A RNA methylation[J].Nature Reviews Genetics,2014,15(5):293-306.
[18] FENG C,LIU Y,WANG G,et al.Crystal structures of the human RNA demethylase ALKBH5 reveal basis for substrate recognition[J].Journal of Biological Chemistry,2014,289(17):11571-11583.
[19] AIK W,SCOTTI JS,CHOI H,et al.Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation[J].Nucleic Acids Research,2014,42(7):4741-4754.
[20] XU C,LIU K,TEMPEL W,et al.Structures of human ALKBH5 demethylase reveal a unique binding mode for specific single-stranded N6-methyladenosine RNA demethylation[J].Journal of Biological Chemistry,2014,289(25):17299-17311.
[21] WU L,WU D,NING J,et al.Changes of N6-methyladenosine modulators promote breast cancer progression[J].BMC Cancer,2019,19(1):326.
[22] ZHANG C,SAMANTA D,LU H,et al.Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA[J].Proceedings of the National Academy of Sciences of the United States of America,2016,113(14):E2047-2056.
[23] ZHANG C,ZHI WI,LU H,et al.Hypoxia-inducible factors regulate pluripotency factor expression by ZNF217-and ALKBH5-mediated modulation of RNA methylation in breast cancer cells[J].Oncotarget,2016,7(40):64527-64542.
[24] LIU H,LYU H,JIANG G,et al.ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes glycolysis and resistance to HER2-targeted therapy in breast cancer[J].Cancer Research,2022,82(21):3974-3986.
[25] LIU Z,CHEN Y,WANG L,et al.ALKBH5 promotes the proliferation of glioma cells via enhancing the mRNA stability of G6PD[J].Neurochemical Research,2021,46(11):3003-3011.
[26] CUI Y,WANG Q,LIN J,et al.miRNA-193a-3p regulates the AKT2 pathway to inhibit the growth and promote the apoptosis of glioma cells by targeting ALKBH5[J].Frontiers in Oncology,2021,11:600451.
[27] LIU B,ZHOU J,WANG C,et al.LncRNA SOX2OT promotes temozolomide resistance by elevating SOX2 expression via ALKBH5-mediated epigenetic regulation in glioblastoma[J].Cell Death Disease,2020,11(5):384.
[28] LI L,YANG M,PU X,et al.ALKBH5-PYCR2 positive feedback loop promotes proneural-mesenchymal transition via proline synthesis in GBM[J].Journal of Cancer,2023,14(9):1579-1591.
[29] TANG W,XU N,ZHOU J,et al.ALKBH5 promotes PD-L1-mediated immune escape through m6A modification of ZDHHC3 in glioma[J].Cell Death Discovery,2022,8(1):497.
[30] CHANG G,XIE GS,MA L,et al.USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5[J].Neuro Oncology,2023,25(5):841-853.
[31] TSUCHIYA K,YOSHIMURA K,IWASHITA Y,et al.m6A demethylase ALKBH5 promotes tumor cell proliferation by destabilizing IGF2BPs target genes and worsens the prognosis of patients with non-small-cell lung cancer[J].Cancer Gene Therapy,2022,29(10):1355-1372.
[32] GUO J,WU Y,DU J,et al.Deregulation of UBE2C-mediated autophagy repression aggravates NSCLC progression[J].Oncogenesis,2018,7(6):49.
[33] ZHANG D,NING J,OKON I,et al.Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer[J].Cell Death Disease,2021,12(6):518.
[34] CHAO Y,SHANG J,JI W.ALKBH5-m6A-FOXM1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia[J].Biochemical and Biophysical Research Communications,2020,521(2):499-506.
[35] YU H,ZHANG Z.ALKBH5-mediated m6A demethylation of lncRNA RMRP plays an oncogenic role in lung adenocarcinoma[J].Mamm Genome,2021,32(3):195-203.
[36] SHEN W,PU J,ZUO Z,et al.The RNA demethylase ALKBH5 promotes the progression and angiogenesis of lung cancer by regulating the stability of the lncRNA PVT1[J].Cancer Cell International,2022,22(1):353.
[37] ZHU H,GAN X,JIANG X,et al.ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2[J].Journal of Cancer Research and Clinical Oncology,2019,38(1):163.
[38] JIANG Y,WAN Y,GONG M,et al.RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF-κB pathway[J].Journal of Cellular and Molecular Medicine,2020,24(11):6137-6148.
[39] NIE S,ZHANG L,LIU J,et al.ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer[J].Journal of Experimental & Clinical Cancer Research, 2021,40(1):284.
[40] SUN R,YUAN L,JIANG Y,et al.ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer[J].Theranostics,2023,13(2):833-848.
[41] WANG J,LI Y,WANG P,et al.Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis[J].Cell Stem Cell,2020,27(1):81-97.e8.
[42] LI R,WU X,XUE K,et al.RNA demethylase ALKBH5 promotes tumorigenesis of t(8;21) acute myeloid leukemia via ITPA m6A modification[J].Biomark Reseaser,2023,11(1):30.
[43] WANG P,WANG J,YAO S,et al.Deubiquitinase USP9X stabilizes RNA m6A demethylase ALKBH5 and promotes acute myeloid leukemia cell survival[J].Journal of Biological Chemistry,2023,299(8):105055.
[44] ZANG J,GUO S,PIAO HY,et al.ALKBH5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncRNA NEAT1[J].Journal of Physiologyand Biochemistry,2019,75(3):379-389.
[45] CHEN C,ZHAI E,LIU Y,et al.ALKBH5-mediated CHAC1 depletion promotes malignant progression and decreases cisplatin-induced oxidative stress in gastric cancer[J].Cancer Cell International,2023,23(1):293.
[46] FANG Y,WU X,GU Y,et al.LINC00659 cooperated with ALKBH5 to accelerate gastric cancer progression by stabilising JAK1 mRNA in an m6A-YTHDF2-dependent manner[J].Clinical and Translational Medicine,2023,13(3):e1205.
[47] WANG S,WANG Y,ZHANG Z,et al.Long non-coding RNA NRON promotes tumor proliferation by regulating ALKBH5 and Nanog in gastric cancer[J].Journal of Cancer,2021,12(22):6861-6872.
[48] GUO T,LIU DF,PENG SH,et al.ALKBH5 promotes colon cancer progression by decreasing methylation of the lncRNA NEAT1[J].American Journal of Translational Research,2020,12(8):4542-4549.
[49] SHEN D,LIN J,XIE Y,et al.RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A-YTHDF2-dependent manner[J].Clinical and Translational Medicine,2023,13(5):e1279.
[50] YU H,YANG X,TANG J,et al.ALKBH5 inhibited cell proliferation and sensitized bladder cancer cells to cisplatin by m6A-CK2α-mediated glycolysis[J].Molecular Therapy-Nucleic Acids,2020,23:27-41.
[51] HE Y,HU H,WANG Y,et al.ALKBH5 inhibits pancreatic cancer motility by decreasing long non-coding RNA KCNK15-AS1 methylation[J].Cellular Physiology and Biochemistry,2018,48(2):838-846.
[52] GUO X,LI K,JIANG W,et al.RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner[J].Molecular Cancer,2020,19(1):91.
[53] TANG B,YANG Y,KANG M,et al.m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling[J].Molecular Cancer,2020,19(1):3.
[54] HUANG R,YANG L,ZHANG Z,et al.RNA m6A demethylase ALKBH5 protects against pancreatic ductal adenocarcinoma via targeting regulators of iron metabolism[J].Frontiers in Cell and Developmental Biology,2021,9:724282.
[55] JIN D,GUO J,WU Y,et al.m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC[J].Molecular Cancer,2020,19(1):40.
[56] SUN Z,SU Z,ZHOU Z,et al.RNA demethylase ALKBH5 inhibits TGF-β-induced EMT by regulating TGF-β/SMAD signaling in non-small cell lung cancer[J].FASEB Journal,2022,36(5):e22283.
[57] ZHANG S,ZHAO BS,ZHOU A,et al.m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program[J].Cancer Cell,2017,31(4):591-606.e6.
[58] SHRIWAS O,PRIYADARSHINI M,SAMAL SK,et al.DDX3 modulates cisplatin resistance in OSCC through ALKBH5-mediated m6A-demethylation of FOXM1 and NANOG[J].Apoptosis,2020,25(3-4):233-246.
[59] FUKUMOTO T,ZHU H,NACARELLI T,et al.N6-methylation of adenosine of FZD10 mRNA contributes to PARP inhibitor resistance[J].Cancer Research,2019,79(11):2812-2820.
[60] SELBEG S,SELI N,KANKURI E,et al.Rational design of novel anticancer small-molecule RNA m6A demethylase ALKBH5 inhibitors[J].ACS Omega,2021,6(20):13310-13320.
[61] MALACRIDA A,RIVARA M,DI DA,et al.3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line[J].Bioorganic & Medicinal Chemistry,2020,28(4):115300.
[62] LI N,KANG Y,WANG L,et al.ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment[J].Proceedings of the National Academy of Sciences of the United States of America,2020,117(33):20159-20170.
[63] PURSLOW JA,NGUYEN TT,KHATIWADA B,et al.N6-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase ALKBH5[J].Science Advances,2021,7(34):eabi8215.
[64] XIE LJ,YANG XT,WANG RL,et al.Identification of flavin mononucleotide as a cell-active artificial N6-methyladenosine RNA demethylase[J].Angewandte Chemie International Edition,2019,58(15):5028-5032.
[65] KHAN S,HE Y,ZHANG X,et al.PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics[J].Oncogene,2020,39(26):4909-4924.

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