Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types.

Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies.

[1]  Kay Hofmann,et al.  MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes , 2016, Molecular cell.

[2]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[3]  Leonardo Morsut,et al.  FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination , 2009, Cell.

[4]  Parantu K. Shah,et al.  A small molecule inhibitor of ubiquitin-specific protease-7 induces apoptosis in multiple myeloma cells and overcomes bortezomib resistance. , 2012, Cancer cell.

[5]  K. Lindsten,et al.  The ubiquitin specific protease 4 (USP4) is a new player in the Wnt signalling pathway , 2009, Journal of cellular and molecular medicine.

[6]  Yu-Ying He,et al.  PTEN in DNA damage repair. , 2012, Cancer letters.

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

[8]  F. Khuri,et al.  The PI3 kinase inhibitor NVP-BKM120 induces GSK3/FBXW7-dependent Mcl-1 degradation, contributing to induction of apoptosis and enhancement of TRAIL-induced apoptosis. , 2013, Cancer letters.

[9]  Prahlad T. Ram,et al.  A pan-cancer proteomic perspective on The Cancer Genome Atlas , 2014, Nature Communications.

[10]  M. Fu,et al.  USP10 inhibits genotoxic NF‐κB activation by MCPIP1‐facilitated deubiquitination of NEMO , 2013, The EMBO journal.

[11]  Somasekar Seshagiri,et al.  Loss of the Tumor Suppressor BAP1 Causes Myeloid Transformation , 2012, Science.

[12]  David Komander,et al.  Breaking the chains: structure and function of the deubiquitinases , 2009, Nature Reviews Molecular Cell Biology.

[13]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C. Su,et al.  MDM2 antagonists synergize broadly and robustly with compounds targeting fundamental oncogenic signaling pathways , 2014, Oncotarget.

[15]  S. Fuchs.  The role of ubiquitin-proteasome pathway in oncogenic signaling. , 2002, Cancer biology & therapy.

[16]  S. Elledge,et al.  Phosphorylation-Dependent Ubiquitination of Cyclin E by the SCFFbw7 Ubiquitin Ligase , 2001, Science.

[17]  C. Bishop,et al.  A novel ubiquitin ligase is deficient in Fanconi anemia , 2003, Nature Genetics.

[18]  P. Nuciforo,et al.  An Atlas of Altered Expression of Deubiquitinating Enzymes in Human Cancer , 2011, PloS one.

[19]  Sudhir Agrawal,et al.  Stabilization of E2F1 protein by MDM2 through the E2F1 ubiquitination pathway , 2005, Oncogene.

[20]  K. Nakayama,et al.  Phosphorylation‐dependent degradation of c‐Myc is mediated by the F‐box protein Fbw7 , 2004, The EMBO journal.

[21]  Xiaodong Huang,et al.  Drugging the undruggables: exploring the ubiquitin system for drug development , 2016, Cell Research.

[22]  L. Vassilev,et al.  In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2 , 2004, Science.

[23]  Anne Floquet,et al.  Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. , 2017, The Lancet. Oncology.

[24]  S. Knapp,et al.  Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. , 2013, Cancer cell.

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

[26]  J Wade Harper,et al.  Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases. , 2007, Molecular cell.

[27]  Ramin Massoumi,et al.  Cyld Inhibits Tumor Cell Proliferation by Blocking Bcl-3-Dependent NF-κB Signaling , 2006, Cell.

[28]  S. Baker,et al.  PTEN and the PI3-kinase pathway in cancer. , 2009, Annual review of pathology.

[29]  Y. Kitagishi,et al.  Connection between Tumor Suppressor BRCA1 and PTEN in Damaged DNA Repair , 2014, Front. Oncol..

[30]  M. Rosner,et al.  An integrated view of cyclin E function and regulation , 2012, Cell cycle.

[31]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[32]  H. Clevers,et al.  Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin signaling through K63-linked ubiquitination of Dvl. , 2010, Molecular cell.

[33]  G. Getz,et al.  GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers , 2011, Genome Biology.

[34]  Björn Schumacher,et al.  p53 in the DNA-Damage-Repair Process. , 2016, Cold Spring Harbor perspectives in medicine.

[35]  K. Hofmann,et al.  When ubiquitin meets ubiquitin receptors: a signalling connection , 2003, Nature Reviews Molecular Cell Biology.

[36]  M. Hung,et al.  Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression , 2013, Cell.

[37]  W. Kaelin,et al.  The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. , 2005, Cancer cell.

[38]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer-associated genes , 2013 .

[39]  C. Crews,et al.  Waste disposal—An attractive strategy for cancer therapy , 2017, Science.

[40]  René Bernards,et al.  A Genomic and Functional Inventory of Deubiquitinating Enzymes , 2005, Cell.

[41]  Sean R. Eddy,et al.  Profile hidden Markov models , 1998, Bioinform..

[42]  Joshua M. Stuart,et al.  The Cancer Genome Atlas Pan-Cancer analysis project , 2013, Nature Genetics.

[43]  Yu Xue,et al.  UUCD: a family-based database of ubiquitin and ubiquitin-like conjugation , 2012, Nucleic Acids Res..

[44]  Daniela Hoeller,et al.  Targeting the ubiquitin system in cancer therapy , 2009, Nature.

[45]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[46]  Robert C. Edgar,et al.  MUSCLE: multiple sequence alignment with high accuracy and high throughput. , 2004, Nucleic acids research.

[47]  K. Nakayama,et al.  Ubiquitin ligases: cell-cycle control and cancer , 2006, Nature Reviews Cancer.

[48]  Il-Jin Kim,et al.  FBXW7 Targets mTOR for Degradation and Cooperates with PTEN in Tumor Suppression , 2008, Science.

[49]  S. Campaner,et al.  Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance , 2012, Cell Division.

[50]  A. Ciechanover,et al.  Functional Interaction between SEL-10, an F-box Protein, and the Nuclear Form of Activated Notch1 Receptor* , 2001, The Journal of Biological Chemistry.

[51]  Steven A. Roberts,et al.  Mutational heterogeneity in cancer and the search for new cancer genes , 2014 .

[52]  V. Quesada,et al.  Deubiquitinases in cancer: new functions and therapeutic options , 2012, Oncogene.

[53]  S. Zienolddiny,et al.  Association of a functional polymorphism in the promoter of the MDM2 gene with risk of nonsmall cell lung cancer , 2006, International journal of cancer.

[54]  Li Ma,et al.  The role of deubiquitinases in breast cancer , 2016, Cancer and Metastasis Reviews.

[55]  Muyang Li,et al.  Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2 , 2003, Science.

[56]  Benjamin J. Raphael,et al.  Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin , 2014, Cell.

[57]  P. Dijke,et al.  The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-β signalling , 2005, Oncogene.