Role of RNA methylation in the regulation of pancreatic cancer stem cells (Review)

Pancreatic cancer stem cells (CSCs) play a key role in the initiation and progression of pancreatic adenocarcinoma (PDAC). CSCs are responsible for resistance to chemotherapy and radiation, and for cancer metastasis. Recent studies have indicated that RNA methylation, a type of RNA modification, predominantly occurring as m6A methylation, plays an important role in controlling the stemness of cancer cells, therapeutic resistance against chemotherapy and radiation therapy, and their overall relevance to a patient's prognosis. CSCs regulate various behaviors of cancer through cell-cell communication by secreting factors, through their receptors, and through signal transduction. Recent studies have shown that RNA methylation is involved in the biology of the heterogeneity of PDAC. The present review provides an update on the current understanding of RNA modification-based therapeutic targets against deleterious PDAC. Several key pathways and agents that can specifically target CSCs have been identified, thus providing novel insights into the early diagnosis and efficient treatment of PDAC.

[1]  R. Garg,et al.  Targeting FTO Suppresses Pancreatic Carcinogenesis via Regulating Stem Cell Maintenance and EMT Pathway , 2022, Cancers.

[2]  C. Lian,et al.  Linc-UROD stabilizes ENO1 and PKM to strengthen glycolysis, proliferation and migration of pancreatic cancer cells , 2022, Translational oncology.

[3]  H. Eguchi,et al.  Emerging roles of long noncoding and circular RNAs in pancreatic ductal adenocarcinoma , 2022, Frontiers in Physiology.

[4]  Yue Zhao,et al.  Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification. , 2022, Pharmacological research.

[5]  H. Eguchi,et al.  Targeting the regulation of aberrant protein production pathway in gastrointestinal cancer treatment , 2022, Frontiers in Oncology.

[6]  Hailing Guo,et al.  METTL3-IGF2BP3-axis mediates the proliferation and migration of pancreatic cancer by regulating spermine synthase m6A modification , 2022, Frontiers in Oncology.

[7]  L. Yao,et al.  RNA modifications: importance in immune cell biology and related diseases , 2022, Signal Transduction and Targeted Therapy.

[8]  Xiao-Rong Liu,et al.  LncRNA MALAT1 regulates METTL3-mediated PD-L1 expression and immune infiltrates in pancreatic cancer , 2022, Frontiers in Oncology.

[9]  Yingting Liu,et al.  Increased expression of METTL3 in pancreatic cancer tissues associates with poor survival of the patients , 2022, World Journal of Surgical Oncology.

[10]  Guo Gao,et al.  METTL3 promotes the growth and metastasis of pancreatic cancer by regulating the m6A modification and stability of E2F5. , 2022, Cellular signalling.

[11]  Jianzhao Liu,et al.  N6-methyladenosine modification-mediated mRNA metabolism is essential for human pancreatic lineage specification and islet organogenesis , 2022, Nature Communications.

[12]  H. Eguchi,et al.  N(6)-methyladenosine methylation-regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma , 2022, Scientific Reports.

[13]  G. Agrimi,et al.  Mitochondrial transport and metabolism of the major methyl donor and versatile cofactor S‐adenosylmethionine, and related diseases: A review† , 2022, IUBMB life.

[14]  D. Ennishi,et al.  Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma , 2022, iScience.

[15]  Degang Kong,et al.  N(6)-methyladenosine-mediated miR-380-3p maturation and upregulation promotes cancer aggressiveness in pancreatic cancer , 2022, Bioengineered.

[16]  Fang Wang,et al.  Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms , 2022, Science Translational Medicine.

[17]  L. Ouyang,et al.  Increased m6A modification of lncRNA DBH-AS1 suppresses pancreatic cancer growth and gemcitabine resistance via the miR-3163/USP44 axis , 2022, Annals of translational medicine.

[18]  J. Oliveira,et al.  METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability , 2022, Cellular and Molecular Life Sciences.

[19]  H. Eguchi,et al.  Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets , 2022, Cancer science.

[20]  Yi Liu,et al.  Long non-coding RNA NEAT1 participates in ventilator-induced lung injury by regulating miR-20b expression , 2022, Molecular medicine reports.

[21]  Liangjing Zhou,et al.  ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer. , 2022, Cancer letters.

[22]  Zhi-wen Zhang,et al.  RNA m6A Demethylase ALKBH5 Protects Against Pancreatic Ductal Adenocarcinoma via Targeting Regulators of Iron Metabolism , 2021, Frontiers in Cell and Developmental Biology.

[23]  Xuanfu Xu,et al.  M6A-mediated up-regulation of LncRNA LIFR-AS1 enhances the progression of pancreatic cancer via miRNA-150-5p/ VEGFA/Akt signaling , 2021, Cell cycle.

[24]  H. Ishii,et al.  Methylosystem for Cancer Sieging Strategy , 2021, Cancers.

[25]  Jie Hong,et al.  Enterotoxigenic Bacteroides fragilis promotes intestinal inflammation and malignancy by inhibiting exosomes-packaged miR-149-3p. , 2021, Gastroenterology.

[26]  Yuanhong Xu,et al.  Quantification of m6A RNA methylation modulators pattern was a potential biomarker for prognosis and associated with tumor immune microenvironment of pancreatic adenocarcinoma , 2021, BMC Cancer.

[27]  H. Eguchi,et al.  Impact of One-Carbon Metabolism-Driving Epitranscriptome as a Therapeutic Target for Gastrointestinal Cancer , 2021, International journal of molecular sciences.

[28]  Xianjun Yu,et al.  Applications of single-cell sequencing in cancer research: progress and perspectives , 2021, Journal of Hematology & Oncology.

[29]  Huaizhi Wang,et al.  N6-methyladenosine (m6A) in pancreatic cancer: Regulatory mechanisms and future direction , 2021, International journal of biological sciences.

[30]  Andrew J. Bannister,et al.  Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia , 2021, Nature.

[31]  Howard Y. Chang,et al.  Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing , 2021, Cell.

[32]  Yu Guo,et al.  ESE3/EHF, a promising target of rosiglitazone, suppresses pancreatic cancer stemness by downregulating CXCR4 , 2021, Gut.

[33]  Cuiping Yang,et al.  The role of m6A modification in the biological functions and diseases , 2021, Signal Transduction and Targeted Therapy.

[34]  S. Rabbani,et al.  Role of Methylation in Pro- and Anti-Cancer Immunity , 2021, Cancers.

[35]  Yixuan Hou,et al.  A novel hypoxic long noncoding RNA KB-1980E6.3 maintains breast cancer stem cell stemness via interacting with IGF2BP1 to facilitate c-Myc mRNA stability , 2021, Oncogene.

[36]  Chengliang Zhou,et al.  Single-cell RNA-seq reveals invasive trajectory and determines cancer stem cell-related prognostic genes in pancreatic cancer , 2021, Bioengineered.

[37]  H. Pei,et al.  M6A Regulatory Genes Play an Important Role in the Prognosis, Progression and Immune Microenvironment of Pancreatic Adenocarcinoma , 2020, Cancer investigation.

[38]  S. Batra,et al.  Metabolic programming of distinct cancer stem cells promotes metastasis of pancreatic ductal adenocarcinoma , 2020, Oncogene.

[39]  Qiulian Wu,et al.  The RNA m6A reader YTHDF2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. , 2020, Cancer discovery.

[40]  Zhonghua Ma,et al.  N6‐methyladenosine (m6A) RNA modification in cancer stem cells , 2020, Stem cells.

[41]  Y. Assaraf,et al.  Surmounting cancer drug resistance: New insights from the perspective of N6-methyladenosine RNA modification. , 2020, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[42]  Jianguo Sun,et al.  Oncogenic miR-20b-5p contributes to malignant behaviors of breast cancer stem cells by bidirectionally regulating CCND1 and E2F1 , 2020, BMC cancer.

[43]  Jie Hou,et al.  Gene Signature and Identification of Clinical Trait-Related m6 A Regulators in Pancreatic Cancer , 2020, Frontiers in Genetics.

[44]  P. Sun,et al.  The m6A Methylation-Regulated AFF4 Promotes Self-Renewal of Bladder Cancer Stem Cells , 2020, Stem cells international.

[45]  Yun Feng,et al.  RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner , 2020, Molecular Cancer.

[46]  Chuan He,et al.  RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia. , 2020, Cell stem cell.

[47]  Gang Yin,et al.  Functions of N6-methyladenosine and its role in cancer , 2019, Molecular Cancer.

[48]  Q. Kan,et al.  The interplay between m6A RNA methylation and noncoding RNA in cancer , 2019, Journal of Hematology & Oncology.

[49]  Y. Miao,et al.  The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion. , 2019, Pathology, research and practice.

[50]  C. Pilarsky,et al.  Chemoresistance in Pancreatic Cancer , 2019, International journal of molecular sciences.

[51]  D. O’Carroll,et al.  Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia , 2019, Cell stem cell.

[52]  M. Muramatsu,et al.  The stem cell-specific intermediate filament nestin missense variation p.A1199P is associated with pancreatic cancer. , 2019, Oncology letters.

[53]  W. Tan,et al.  Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression , 2019, Nature Communications.

[54]  Q. Lan,et al.  The Critical Role of RNA m6A Methylation in Cancer. , 2019, Cancer research.

[55]  R. Turkington,et al.  Pancreatic cancer: A review of clinical diagnosis, epidemiology, treatment and outcomes , 2018, World journal of gastroenterology.

[56]  L. Rich,et al.  An ABCG2 non-substrate anticancer agent FL118 targets drug-resistant cancer stem-like cells and overcomes treatment resistance of human pancreatic cancer , 2018, Journal of experimental & clinical cancer research : CR.

[57]  S. Arab,et al.  Phytochemicals, withaferin A and carnosol, overcome pancreatic cancer stem cells as c-Met inhibitors. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[58]  B. Sáinz,et al.  The Epigenetic Landscape of Pancreatic Cancer Stem Cells , 2018, Epigenomes.

[59]  T. Ishiwata,et al.  Pancreatic cancer stem cells: features and detection methods , 2018, Pathology & Oncology Research.

[60]  A. Stoita,et al.  Challenges in diagnosis of pancreatic cancer , 2018, World journal of gastroenterology.

[61]  Hongchuan Jin,et al.  N6-methyladenosine links RNA metabolism to cancer progression , 2018, Cell Death & Disease.

[62]  H. Ishii,et al.  The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. , 2017, International journal of oncology.

[63]  Samie R Jaffrey,et al.  Rethinking m6A Readers, Writers, and Erasers. , 2017, Annual review of cell and developmental biology.

[64]  Yi Zhang,et al.  TET-mediated active DNA demethylation: mechanism, function and beyond , 2017, Nature Reviews Genetics.

[65]  Chuan He,et al.  m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. , 2017, Cancer cell.

[66]  Zhike Lu,et al.  m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells , 2017, Cell reports.

[67]  I. Hellmann,et al.  Comparative Analysis of Single-Cell RNA Sequencing Methods , 2016, bioRxiv.

[68]  Bo Huang,et al.  Long non-coding RNA NEAT1 facilitates pancreatic cancer progression through negative modulation of miR-506-3p. , 2017, Biochemical and biophysical research communications.

[69]  R. Andersson,et al.  Pancreatic cancer: yesterday, today and tomorrow. , 2016, Future oncology.

[70]  Chuanzhao Zhang,et al.  Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m6A-demethylation of NANOG mRNA , 2016, Proceedings of the National Academy of Sciences.

[71]  S. Dalton,et al.  Metabolic Reprogramming of Stem Cell Epigenetics. , 2015, Cell stem cell.

[72]  Bert A van der Reijden,et al.  5-Hydroxymethylcytosine: An epigenetic mark frequently deregulated in cancer. , 2015, Biochimica et biophysica acta.

[73]  Thomas J. Hudson,et al.  Corrigendum: Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia , 2014, Nature.

[74]  O. Elemento,et al.  Comprehensive Analysis of mRNA Methylation Reveals Enrichment in 3′ UTRs and near Stop Codons , 2012, Cell.

[75]  M. Kupiec,et al.  Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq , 2012, Nature.

[76]  A. Masamune,et al.  The homeobox gene MSX2 determines chemosensitivity of pancreatic cancer cells via the regulation of transporter gene ABCG2 , 2012, Journal of cellular physiology.

[77]  T. Welling,et al.  c-Met is a marker of pancreatic cancer stem cells and therapeutic target. , 2011, Gastroenterology.

[78]  Chengqi Yi,et al.  N6-Methyladenosine in Nuclear RNA is a Major Substrate of the Obesity-Associated FTO , 2011, Nature chemical biology.

[79]  K. Mimori,et al.  CD13 is a therapeutic target in human liver cancer stem cells. , 2010, The Journal of clinical investigation.

[80]  K. Mimori,et al.  Cancer stem cells and chemoradiation resistance , 2008, Cancer science.

[81]  K. Mimori,et al.  CD133+CD44+ Population Efficiently Enriches Colon Cancer Initiating Cells , 2008, Annals of Surgical Oncology.

[82]  S. Batra,et al.  Human RNA polymerase II-associated factor complex: dysregulation in cancer , 2007, Oncogene.

[83]  J. Dick,et al.  A human colon cancer cell capable of initiating tumour growth in immunodeficient mice , 2007, Nature.

[84]  Mark Johnston,et al.  The Paf1 Complex Is Essential for Histone Monoubiquitination by the Rad6-Bre1 Complex, Which Signals for Histone Methylation by COMPASS and Dot1p* , 2003, Journal of Biological Chemistry.

[85]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[86]  A. Feinberg,et al.  Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. , 1985, Science.

[87]  M. Minden,et al.  Acute myeloblastic leukemia considered as a clonal hemopathy. , 1979, Blood cells.

[88]  R. Desrosiers,et al.  Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[89]  Vineet Gupta,et al.  Isolation of Lipid Raft Proteins from CD133+ Cancer Stem Cells. , 2017, Methods in molecular biology.

[90]  R. Perry,et al.  Existence of Methylated Messenger RNA in Mouse L Cells , 1974 .