The miR-17∼92 microRNA Cluster Is a Global Regulator of Tumor Metabolism.

A central hallmark of cancer cells is the reprogramming of cellular metabolism to meet the bioenergetic and biosynthetic demands of malignant growth. Here, we report that the miR-17∼92 microRNA (miRNA) cluster is an oncogenic driver of tumor metabolic reprogramming. Loss of miR-17∼92 in Myc(+) tumor cells leads to a global decrease in tumor cell metabolism, affecting both glycolytic and mitochondrial metabolism, whereas increased miR-17∼92 expression is sufficient to drive increased nutrient usage by tumor cells. We mapped the metabolic control element of miR-17∼92 to the miR-17 seed family, which influences cellular metabolism and mammalian target of rapamycin complex 1 (mTORC1) signaling through negative regulation of the LKB1 tumor suppressor. miR-17-dependent tuning of LKB1 levels regulates both the metabolic potential of Myc(+) lymphomas and tumor growth in vivo. Our results establish metabolic reprogramming as a central function of the oncogenic miR-17∼92 miRNA cluster that drives the progression of MYC-dependent tumors.

[1]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[2]  Bruno Rossion,et al.  Figures and figure supplements , 2014 .

[3]  Abhishek K. Jha,et al.  Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. , 2015, Immunity.

[4]  B. Faubert,et al.  Myc induces expression of glutamine synthetase through promoter demethylation , 2015 .

[5]  D. Sabatini,et al.  An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis , 2015, Cell.

[6]  Daniel E Bauer,et al.  ATP citrate lyase inhibition can suppress tumor cell growth. , 2005, Cancer cell.

[7]  B. Faubert,et al.  PGC-1α supports glutamine metabolism in breast cancer , 2013, Cancer & Metabolism.

[8]  Jiahuai Han,et al.  Molecular and Cellular Pathobiology the Mir-17-92 Cluster of Micrornas Confers Tumorigenicity by Inhibiting Oncogene-induced Senescence , 2022 .

[9]  Stuart H. Orkin,et al.  A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs , 2010, Cell.

[10]  B. Nielsen,et al.  microRNA-17 Is the Most Up-Regulated Member of the miR-17-92 Cluster during Early Colon Cancer Evolution , 2015, PloS one.

[11]  A. Ashworth,et al.  The mouse Peutz-Jeghers syndrome gene Lkb1 encodes a nuclear protein kinase. , 1999, Human molecular genetics.

[12]  R. Gascoyne,et al.  MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. , 2009, Blood.

[13]  Doron Betel,et al.  Genetic dissection of the miR-17~92 cluster of microRNAs in Myc-induced B-cell lymphomas. , 2009, Genes & development.

[14]  Takashi Tsukamoto,et al.  Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. , 2012, Cell metabolism.

[15]  Junying Yuan,et al.  LKB1 — A master tumour suppressor of the small intestine and beyond , 2002, Nature Reviews Cancer.

[16]  R. DePinho,et al.  The LKB1 tumor suppressor negatively regulates mTOR signaling. , 2004, Cancer cell.

[17]  Robert Tibshirani,et al.  A network model of a cooperative genetic landscape in brain tumors. , 2009, JAMA.

[18]  R. Gregory,et al.  A Biogenesis Step Upstream of Microprocessor Controls miR-17∼92 Expression , 2015, Cell.

[19]  S. Lowe,et al.  miR-19 is a key oncogenic component of mir-17-92. , 2009, Genes & development.

[20]  Michael C. Ostrowski,et al.  MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. , 2010, Molecular cell.

[21]  Kathryn A. O’Donnell,et al.  c-Myc-regulated microRNAs modulate E2F1 expression , 2005, Nature.

[22]  M. V. Vander Heiden,et al.  Aerobic glycolysis: meeting the metabolic requirements of cell proliferation. , 2011, Annual review of cell and developmental biology.

[23]  Lin He,et al.  mir‐17‐92: a polycistronic oncomir with pleiotropic functions , 2013, Immunological reviews.

[24]  Z. Fei,et al.  Integrative Analysis of miRNA and mRNA Profiles in Response to Ethylene in Rose Petals during Flower Opening , 2013, PloS one.

[25]  D. Bartel,et al.  Predicting effective microRNA target sites in mammalian mRNAs , 2015, eLife.

[26]  T. Mäkelä,et al.  Molecular mechanisms of tumor suppression by LKB1 , 2011, FEBS letters.

[27]  J. Ouyang,et al.  MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy , 2014, Tumor Biology.

[28]  G. Mills,et al.  LKB1 is a central regulator of tumor initiation and pro-growth metabolism in ErbB2-mediated breast cancer , 2013, Cancer & Metabolism.

[29]  Charles Y. Lin,et al.  Taming of the beast: shaping Myc-dependent amplification. , 2015, Trends in cell biology.

[30]  M. V. Heiden,et al.  Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells , 2015, Cell.

[31]  W. Filipowicz,et al.  Regulation of mRNA translation and stability by microRNAs. , 2010, Annual review of biochemistry.

[32]  Takla Griss,et al.  Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α , 2014, Proceedings of the National Academy of Sciences.

[33]  S. Landais,et al.  Oncogenic potential of the miR-106-363 cluster and its implication in human T-cell leukemia. , 2007, Cancer research.

[34]  S. Gabriel,et al.  Pan-cancer patterns of somatic copy-number alteration , 2013, Nature Genetics.

[35]  T. Rabbitts,et al.  Translocation joins c-myc and immunoglobulin γ1 genes in a Burkitt lymphoma revealing a third exon in the c-myc oncogene , 1983, Nature.

[36]  S. Barrans,et al.  Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  S. Lowe,et al.  Probing tumor phenotypes using stable and regulated synthetic microRNA precursors , 2005, Nature Genetics.

[38]  R. Shaw,et al.  The LKB1–AMPK pathway: metabolism and growth control in tumour suppression , 2009, Nature Reviews Cancer.

[39]  Min Wu,et al.  Multiparameter metabolic analysis reveals a close link between attenuated mitochondrial bioenergetic function and enhanced glycolysis dependency in human tumor cells. , 2007, American journal of physiology. Cell physiology.

[40]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[41]  Takla Griss,et al.  AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. , 2013, Cell metabolism.

[42]  D. Green,et al.  c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells , 2012, Cell.

[43]  Charles Y. Lin,et al.  Transcriptional Amplification in Tumor Cells with Elevated c-Myc , 2012, Cell.

[44]  K. Ohuchida,et al.  MicroRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion , 2010, Cancer biology & therapy.

[45]  Lin He,et al.  mir-17-92, a cluster of miRNAs in the midst of the cancer network. , 2010, The international journal of biochemistry & cell biology.

[46]  Russell G. Jones,et al.  Tumor suppressors and cell metabolism: a recipe for cancer growth. , 2009, Genes & development.

[47]  Ralph J Deberardinis,et al.  Brick by brick: metabolism and tumor cell growth. , 2008, Current opinion in genetics & development.

[48]  S. Lowe,et al.  A microRNA polycistron as a potential human oncogene , 2005, Nature.

[49]  L. Staudt,et al.  Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics , 2012, Nature.

[50]  林下 陽二.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation , 2006 .

[51]  Lengchen Hou,et al.  MicroRNA-17 promotes normal ovarian cancer cells to cancer stem cells development via suppression of the LKB1-p53-p21/WAF1 pathway , 2015, Tumor Biology.

[52]  Benjamin E. Gross,et al.  The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. , 2012, Cancer discovery.

[53]  N. Sonenberg,et al.  Pervasive and cooperative deadenylation of 3'UTRs by embryonic microRNA families. , 2010, Molecular cell.

[54]  Chin-Lee Wu,et al.  mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome , 2009, Proceedings of the National Academy of Sciences.

[55]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[56]  J. M. Thomson,et al.  miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. , 2011, Genes & development.

[57]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[58]  Steven J. M. Jones,et al.  Comprehensive molecular profiling of lung adenocarcinoma , 2014, Nature.

[59]  A. McKenna,et al.  Integrative eQTL-Based Analyses Reveal the Biology of Breast Cancer Risk Loci , 2013, Cell.

[60]  Takla Griss,et al.  Differential effects of AMPK agonists on cell growth and metabolism , 2014, Oncogene.

[61]  Anthony Mancuso,et al.  Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction , 2008, Proceedings of the National Academy of Sciences.

[62]  C. Dang,et al.  MYC, Metabolism, and Cancer. , 2015, Cancer discovery.

[63]  Alexey Sergushichev,et al.  Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth. , 2015, Molecular cell.

[64]  Tsung-Cheng Chang,et al.  c-Myc suppression of miR-23 enhances mitochondrial glutaminase and glutamine metabolism , 2009, Nature.

[65]  D. Tollervey,et al.  Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding , 2013, Cell.

[66]  S. Weinberg,et al.  Targeting mitochondria metabolism for cancer therapy. , 2015, Nature chemical biology.

[67]  Leah E. Mechanic,et al.  Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer , 2011, Oncogene.

[68]  Hiroyuki Tagawa,et al.  Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. , 2004, Cancer research.

[69]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[70]  E. Furth,et al.  Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster , 2006, Nature Genetics.

[71]  D. Dill,et al.  MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. , 2014, Cancer cell.

[72]  M. Routbort,et al.  Prognostic value of MYC rearrangement in cases of B‐cell lymphoma, unclassifiable, with features intermediate between diffuse large B‐cell lymphoma and Burkitt lymphoma , 2012, Cancer.

[73]  P. Sethupathy,et al.  Expression determinants of mammalian argonaute proteins in mediating gene silencing , 2011, Nucleic acids research.

[74]  Peter J. Woolf,et al.  GAGE: generally applicable gene set enrichment for pathway analysis , 2009, BMC Bioinformatics.

[75]  D. Green,et al.  The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. , 2011, Immunity.