The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer.

The PI3-kinase/AKT pathway integrates signals from external cellular stimuli to regulate essential cellular functions, and is frequently aberrantly activated in human cancers. Recent research demonstrates that tight regulation of the epigenome is critical in preserving and restricting transcriptional activation, which can impact cellular growth and proliferation. In this review we examine mechanisms by which the PI3K/AKT pathway regulates the epigenome to promote oncogenesis, and highlight how connections between PI3K/AKT and the epigenome may impact the future therapeutic treatment of cancers featuring a hyperactivated PI3K/AKT pathway.

[1]  Daniela Gabriel,et al.  Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity , 2008, Molecular Cancer Therapeutics.

[2]  M. Hung,et al.  Akt-Mediated Phosphorylation of EZH2 Suppresses Methylation of Lysine 27 in Histone H3 , 2005, Science.

[3]  S. Dhanasekaran,et al.  Targeting the MLL complex in castration resistant prostate cancer , 2015, Nature Medicine.

[4]  S. Fröhling,et al.  Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia , 2014, Leukemia.

[5]  M. Bosenberg,et al.  DNMT3b Modulates Melanoma Growth by Controlling Levels of mTORC2 Component RICTOR. , 2016, Cell reports.

[6]  D. Gary Gilliland,et al.  The Retinoblastoma Binding Protein RBP2 Is an H3K4 Demethylase , 2007, Cell.

[7]  Michael L. Wang,et al.  Phase II study of an AKT inhibitor MK2206 in patients with relapsed or refractory lymphoma , 2014, British journal of haematology.

[8]  Jean J. Zhao,et al.  PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting , 2014, Nature Reviews Cancer.

[9]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[10]  C. Prives,et al.  MOZ increases p53 acetylation and premature senescence through its complex formation with PML , 2013, Proceedings of the National Academy of Sciences.

[11]  Ching-Chow Chen,et al.  Akt Phosphorylation of p300 at Ser-1834 Is Essential for Its Histone Acetyltransferase and Transcriptional Activity , 2005, Molecular and Cellular Biology.

[12]  P. Cohen,et al.  Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase‐1 and p70 S6 kinase , 1996, FEBS letters.

[13]  Sathish Kumar Mungamuri,et al.  Chromatin modifications sequentially enhance ErbB2 expression in ErbB2-positive breast cancers. , 2013, Cell reports.

[14]  M. Greenberg,et al.  Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor , 1999, Cell.

[15]  Yi Zhang,et al.  Role of Bmi-1 and Ring1A in H2A ubiquitylation and Hox gene silencing. , 2005, Molecular cell.

[16]  Pixu Liu,et al.  Targeting the phosphoinositide 3-kinase pathway in cancer , 2009, Nature Reviews Drug Discovery.

[17]  G. Mills,et al.  SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. , 2015, Journal of the National Cancer Institute.

[18]  N. Gray,et al.  Functional characterization of an isoform-selective inhibitor of PI3K-p110β as a potential anticancer agent. , 2012, Cancer discovery.

[19]  P. Workman,et al.  Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941 , 2009, Molecular Cancer Therapeutics.

[20]  R. Deng,et al.  Inhibition of DNA methyltransferase as a novel therapeutic strategy to overcome acquired resistance to dual PI3K/mTOR inhibitors , 2015, Oncotarget.

[21]  M. Vidal,et al.  Role of histone H2A ubiquitination in Polycomb silencing , 2004, Nature.

[22]  K. Mulder,et al.  Menin links estrogen receptor activation to histone H3K4 trimethylation. , 2006, Cancer research.

[23]  Yan Liu,et al.  Akt kinase targets the association of CBP with histone H3 to regulate the acetylation of lysine K18 , 2013, FEBS letters.

[24]  Ryan D. Morin,et al.  Somatic mutation of EZH2 (Y641) in Follicular and Diffuse Large B-cell Lymphomas of Germinal Center Origin , 2010, Nature Genetics.

[25]  P. Jagodziński,et al.  The role of DNA methylation in cancer development. , 2006, Folia histochemica et cytobiologica.

[26]  Bo Wen,et al.  Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo. , 2015, Cancer cell.

[27]  Y. Taya,et al.  Monocytic Leukemia Zinc Finger (MOZ) Interacts with p53 to Induce p21 Expression and Cell-cycle Arrest* , 2009, Journal of Biological Chemistry.

[28]  B. Doble,et al.  Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci* , 2010, The Journal of Biological Chemistry.

[29]  Hélène Rogniaux,et al.  Disruption of Dnmt1/PCNA/UHRF1 Interactions Promotes Tumorigenesis from Human and Mice Glial Cells , 2010, PloS one.

[30]  S. Dhanasekaran,et al.  The polycomb group protein EZH2 is involved in progression of prostate cancer , 2002, Nature.

[31]  Debashis Ghosh,et al.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Ji Luo,et al.  The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism , 2006, Nature Reviews Genetics.

[33]  R. Copeland,et al.  Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas , 2010, Proceedings of the National Academy of Sciences.

[34]  A. Shilatifard,et al.  A COMPASS in the voyage of defining the role of trithorax/MLL‐containing complexes: Linking leukemogensis to covalent modifications of chromatin , 2005, Journal of cellular biochemistry.

[35]  Andrew P. Feinberg,et al.  Epigenetic modulators, modifiers and mediators in cancer aetiology and progression , 2016, Nature Reviews Genetics.

[36]  K. Inoki,et al.  TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling , 2002, Nature Cell Biology.

[37]  M. Szyf,et al.  Role of epigenetics in cancer initiation and progression. , 2011, Advances in experimental medicine and biology.

[38]  A. Italiano,et al.  Phase 1 Study of Tazemetostat (EPZ-6438), an Inhibitor of Enhancer of Zeste-Homolog 2 (EZH2): Preliminary Safety and Activity in Relapsed or Refractory Non-Hodgkin Lymphoma (NHL) Patients , 2015 .

[39]  Xiaodong Cheng,et al.  A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability , 2011, Nature Structural &Molecular Biology.

[40]  Charles Y. Lin,et al.  PI3K/AKT Signaling Regulates H3K4 Methylation in Breast Cancer. , 2016, Cell reports.

[41]  B. Garcia,et al.  Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. , 2014, Blood.

[42]  Timothy J. Griffin,et al.  Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40 , 2007, Nature Cell Biology.

[43]  Robert A Copeland,et al.  Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. , 2013, Blood.

[44]  A. Zelenetz,et al.  Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. , 2014, The New England journal of medicine.

[45]  Kirk C. Hansen,et al.  CBP / p300-mediated acetylation of histone H3 on lysine 56 , 2009, Nature.

[46]  Shuai Li,et al.  Structural basis for activity regulation of MLL family methyltransferases , 2016, Nature.

[47]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[48]  R. Johnstone,et al.  New and emerging HDAC inhibitors for cancer treatment. , 2014, The Journal of clinical investigation.

[49]  Qiang Yu,et al.  Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. , 2007, Genes & development.

[50]  B. Spencer‐Dene,et al.  Requirement for Interaction of PI3-Kinase p110 alpha with RAS in Lung Tumor Maintenance , 2013 .

[51]  Hailing Cheng,et al.  The p110α and p110β isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. , 2012, Genes & development.

[52]  John L Markley,et al.  Molecular insights into the recognition of N-terminal histone modifications by the BRPF1 bromodomain. , 2014, Journal of molecular biology.

[53]  K. Helin,et al.  RBP2 Belongs to a Family of Demethylases, Specific for Tri-and Dimethylated Lysine 4 on Histone 3 , 2007, Cell.

[54]  H. Putter,et al.  Histone trimethylation at H3K4, H3K9 and H4K20 correlates with patient survival and tumor recurrence in early-stage colon cancer , 2014, BMC Cancer.

[55]  Yang Shi,et al.  Emerging roles for chromatin as a signal integration and storage platform , 2013, Nature Reviews Molecular Cell Biology.

[56]  G. Poda,et al.  Small-molecule inhibition of MLL activity by disruption of its interaction with WDR5 , 2012, The Biochemical journal.

[57]  R. Schneider,et al.  Cancers with wrong HATs: the impact of acetylation. , 2013, Briefings in functional genomics.

[58]  I. Flinn,et al.  Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. , 2016, The Lancet. Oncology.

[59]  G. Sledge,et al.  Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models , 2012, Breast Cancer Research and Treatment.

[60]  Jing-Yuan Fang,et al.  Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer , 2009, International Journal of Colorectal Disease.

[61]  B. Spencer‐Dene,et al.  Requirement for Interaction of PI3-Kinase p110α with RAS in Lung Tumor Maintenance , 2013, Cancer cell.

[62]  J. Aronson.  Safety , 2009, BMJ : British Medical Journal.

[63]  R. Schneider,et al.  Histone modifiers in cancer: friends or foes? , 2011, Genes & cancer.

[64]  Z. Zou,et al.  Combination of Gefitinib and DNA Methylation Inhibitor Decitabine Exerts Synergistic Anti-Cancer Activity in Colon Cancer Cells , 2014, PloS one.

[65]  Tim J. Wigle,et al.  Selective Inhibition of EZH2 by EPZ-6438 Leads to Potent Antitumor Activity in EZH2-Mutant Non-Hodgkin Lymphoma , 2014, Molecular Cancer Therapeutics.

[66]  F. Lan,et al.  Regulation of LSD1 histone demethylase activity by its associated factors. , 2005, Molecular cell.

[67]  J. Olson,et al.  HDAC and PI3K Antagonists Cooperate to Inhibit Growth of MYC-Driven Medulloblastoma. , 2016, Cancer cell.

[68]  Jiahai Zhang,et al.  Combinatorial readout of unmodified H3R2 and acetylated H3K14 by the tandem PHD finger of MOZ reveals a regulatory mechanism for HOXA9 transcription. , 2012, Genes & development.

[69]  Cheryl H. Arrowsmith,et al.  Prevalent p53 mutants co-opt chromatin pathways to drive cancer growth , 2015, Nature.