title: Active CREB1 promotes a malignant TGFβ2 autocrine loop in glioblastoma.
abstract: In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma.
  
  
  CONCLUSIONS
  TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies.
authors.affiliation: Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Rodón
authors.affiliation: Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Gonzàlez-Juncà
authors.affiliation: Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: María del Mar
authors.initials: Mdel M
authors.lastname: Inda
authors.affiliation: Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: Ada
authors.initials: A
authors.lastname: Sala-Hojman
authors.affiliation: Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez-Sáez
authors.affiliation: Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain. Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. jseoane@vhio.net.
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001483:Base Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D059372:Nucleotide Motifs; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015533:Transcriptional Activation; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D019869:Phosphatidylinositol 3-Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa