2. Academic Validation
  3. pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

  • Nat Commun. 2022 Nov 11;13(1):6840. doi: 10.1038/s41467-022-34529-6.
Olga Boix 1,  Marion Martinez 1,  Santiago Vidal 2,  Marta Giménez-Alejandre 1,  Lluís Palenzuela 1,  Laura Lorenzo-Sanz 3,  Laura Quevedo 4,  Olivier Moscoso 5,  Jorge Ruiz-Orera 6,  Pilar Ximénez-Embún 7,  Nikaoly Ciriaco 5,  Paolo Nuciforo 8,  Camille Stephan-Otto Attolini 9,  M Mar Albà 10 11,  Javier Muñoz 7,  Tian V Tian 12,  Ignacio Varela 4,  Ana Vivancos 13,  Santiago Ramón Y Cajal 5,  Purificación Muñoz 3,  Carmen Rivas 2 14,  María Abad 15
Affiliations

Affiliations

  • 1 Cellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 2 Centro de Investigación en Medicina Molecular (CIMUS), Universidad de Santiago de Compostela and Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
  • 3 Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
  • 4 Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria - CSIC, Santander, Spain.
  • 5 Department of Pathology, Vall d'Hebron University Hospital, Translational Molecular Pathology, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona and Spanish Biomedical Research Network Centre in Oncology (CIBERONC), Barcelona, Spain.
  • 6 Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
  • 7 Proteomics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 8 Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 9 Bioinformatics-Biostatistics Unit, Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 10 IMIM - Hospital del Mar Medical Research Institute, Barcelona, Spain.
  • 11 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
  • 12 Noncolorectal Gastrointestinal Cancer Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 13 Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
  • 14 Departamento de Biología Molecular y Celular, Centro Nacional de Biotecnología (CNB), CSIC, Darwin 3, 28049, Madrid, Spain.
  • 15 Cellular Plasticity and Cancer Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. mabad@vhio.net.
PMID: 36369429 DOI: 10.1038/s41467-022-34529-6
Abstract

The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin Cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for Cancer.

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