PPARδ Elicits Ligand-Independent Repression of Trefoil Factor Family to Limit Prostate Cancer Growth.

The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation, and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here, we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a noncanonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 with prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.Significance: These findings challenge the presumption that the function of the nuclear receptor PPARβ/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399-409. ©2017 AACR.

[1]  J. Peters,et al.  Peroxisome proliferator‐activated receptor‐β/δ inhibits human neuroblastoma cell tumorigenesis by inducing p53‐ and SOX2‐mediated cell differentiation , 2017, Molecular carcinogenesis.

[2]  N. Schultz,et al.  The metabolic co-regulator PGC1α suppresses prostate cancer metastasis , 2016, Nature Cell Biology.

[3]  N. Dünker,et al.  Trefoil factor family peptides – friends or foes? , 2015, Biomolecular concepts.

[4]  J. Peters,et al.  Establishing the Role of PPARβ/δ in Carcinogenesis , 2015, Trends in Endocrinology & Metabolism.

[5]  J. Peters,et al.  Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms , 2015, Oncotarget.

[6]  Angharad Evans,et al.  Trefoil factor 3 (TFF3) enhances the oncogenic characteristics of prostate carcinoma cells and reduces sensitivity to ionising radiation. , 2015, Cancer letters.

[7]  C. Cordon-Cardo,et al.  Methodological aspects of the molecular and histological study of prostate cancer: Focus on PTEN , 2015, Methods.

[8]  S. Terry,et al.  Clinical value of ERG, TFF3, and SPINK1 for molecular subtyping of prostate cancer , 2015, Cancer.

[9]  Ming Liu,et al.  [Expressions of TFF1 and TFF3 in prostate cancer and prostatic intraepithelial neoplasia and their clinical significance]. , 2015, Zhonghua nan ke xue = National journal of andrology.

[10]  J. Peters,et al.  Targeting Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) for Cancer Chemoprevention , 2015, Current Pharmacology Reports.

[11]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[12]  J. Peters,et al.  Activation of Peroxisome Proliferator-Activated Receptor-β/δ (PPAR-β/δ) Inhibits Human Breast Cancer Cell Line Tumorigenicity , 2014, Molecular Cancer Therapeutics.

[13]  M. Rubin,et al.  V-ets erythroblastosis virus E26 oncogene homolog (avian)/Trefoil factor 3/high-molecular-weight cytokeratin triple immunostain: a novel tissue-based biomarker in prostate cancer with potential clinical application. , 2013, Human pathology.

[14]  Kyucheol Cho,et al.  PPARδ promotes oncogenic redirection of TGF-β1 signaling through the activation of the ABCA1-Cav1 pathway , 2013, Cell cycle.

[15]  T. Zhu,et al.  Trefoil factor 1 suppression of E-CADHERIN enhances prostate carcinoma cell invasiveness and metastasis. , 2013, Cancer letters.

[16]  J. V. Vanden Heuvel,et al.  Role of Peroxisome Proliferator-Activated Receptor β/δ and B-Cell Lymphoma-6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells , 2013, PPAR research.

[17]  Pier Paolo Pandolfi,et al.  Cancer metabolism: fatty acid oxidation in the limelight , 2013, Nature Reviews Cancer.

[18]  M. Scharfe,et al.  Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion , 2012, Oncogene.

[19]  G. Hager,et al.  Analysis of the peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) cistrome reveals novel co-regulatory role of ATF4 , 2012, BMC Genomics.

[20]  P. Puigserver,et al.  A metabolic prosurvival role for PML in breast cancer. , 2012, The Journal of clinical investigation.

[21]  P. Pandolfi,et al.  A PML–PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance , 2012, Nature Medicine.

[22]  A. Carracedo,et al.  Is the Bench Getting Closer to the Bedside in the War on Cancer? A Quick Look at Prostate Cancer , 2012, Front. Endocrin..

[23]  J. Peters,et al.  The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention , 2012, Nature Reviews Cancer.

[24]  J. Peters,et al.  Dissecting the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in colon, breast, and lung carcinogenesis , 2011, Cancer and Metastasis Reviews.

[25]  K. Wagner,et al.  Peroxisome proliferator‐activated receptor β/δ (PPARβ/δ) is highly expressed in liposarcoma and promotes migration and proliferation , 2011, The Journal of pathology.

[26]  L. Nagy,et al.  PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation☆ , 2011, Biochimica et biophysica acta.

[27]  H. Blöcker,et al.  Genomewide Analyses Define Different Modes of Transcriptional Regulation by Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ) , 2011, PloS one.

[28]  K. D. Sørensen,et al.  Promoter hypomethylation and upregulation of trefoil factors in prostate cancer , 2010, International journal of cancer.

[29]  S. Amin,et al.  Ligand activation of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) inhibits cell growth in a mouse mammary gland cancer cell line. , 2010, Cancer letters.

[30]  J. Auwerx,et al.  The intestinal nuclear receptor signature with epithelial localization patterns and expression modulation in tumors. , 2010, Gastroenterology.

[31]  H. Zhang,et al.  Knockdown of peroxisome proliferator-activated receptor-β induces less differentiation and enhances cell–fibronectin adhesion of colon cancer cells , 2010, Oncogene.

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

[33]  S. Kjellev.  The trefoil factor family – small peptides with multiple functionalities , 2009, Cellular and Molecular Life Sciences.

[34]  J. Ward,et al.  Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) inhibits chemically induced skin tumorigenesis. , 2008, Carcinogenesis.

[35]  A. Abdou,et al.  pS2 (TFF1) expression in prostate carcinoma: correlation with steroid receptor status   , 2008, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[36]  M. Tretiakova,et al.  Peroxisome proliferator-activated receptor-delta induces cell proliferation by a cyclin E1-dependent mechanism and is up-regulated in thyroid tumors. , 2008, Cancer research.

[37]  T. Willson,et al.  Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands do not potentiate growth of human cancer cell lines , 2007 .

[38]  R. Moll,et al.  Growth of transgenic RAF-induced lung adenomas is increased in mice with a disrupted PPARβ/δ gene , 2007 .

[39]  Sadao Takahashi,et al.  New Therapeutic Target for Metabolic Syndrome: PPARδ , 2007 .

[40]  Béatrice Desvergne,et al.  From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. , 2006, Progress in lipid research.

[41]  S. Poulsen,et al.  Plasma Levels of Trefoil Factors are Increased in Patients with Advanced Prostate Cancer , 2006, Clinical Cancer Research.

[42]  Jason A. Koutcher,et al.  Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis , 2005, Nature.

[43]  S. Horvath,et al.  Trefoil factor 3 is overexpressed in human prostate cancer , 2004, The Prostate.

[44]  Jun Luo,et al.  Trefoil factor 3 overexpression in prostatic carcinoma: Prognostic importance using tissue microarrays , 2004, The Prostate.

[45]  A. Harris,et al.  Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. , 2004, Cancer research.

[46]  G. Barish,et al.  PPARs and the complex journey to obesity , 2004, Nature Medicine.

[47]  J. Ward,et al.  Peroxisome proliferator–activated receptor-δ attenuates colon carcinogenesis , 2004, Nature Medicine.

[48]  Yanhong Shi,et al.  The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  R. Evans,et al.  Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  K. Kinzler,et al.  PPARδ Is an APC-Regulated Target of Nonsteroidal Anti-Inflammatory Drugs , 1999, Cell.

[51]  B. Spiegelman,et al.  Differential activation of adipogenesis by multiple PPAR isoforms. , 1996, Genes & development.

[52]  H. Land,et al.  Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. , 1990, Nucleic acids research.

[53]  F. Gonzalez,et al.  Models and Technologies Activation of Peroxisome Proliferator-Activated Receptor-b / d ( PPAR-b / d ) Inhibits Human Breast Cancer Cell Line Tumorigenicity , 2014 .

[54]  Sadao Takahashi,et al.  New therapeutic target for metabolic syndrome: PPARdelta. , 2007, Endocrine journal.

[55]  T. Willson,et al.  Peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) ligands do not potentiate growth of human cancer cell lines. , 2007, Carcinogenesis.

[56]  R. Moll,et al.  Growth of transgenic RAF-induced lung adenomas is increased in mice with a disrupted PPARbeta/delta gene. , 2007, International journal of oncology.

[57]  Christopher K. Glass,et al.  Combinatorial roles of nuclear receptors in inflammation and immunity , 2006, Nature Reviews Immunology.

[58]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.

[59]  K. Kinzler,et al.  PPAR d Is an APC-Regulated Target of Nonsteroidal Anti-Inflammatory Drugs , 1999 .

[60]  W. Wahli,et al.  Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. , 1996, Endocrinology.