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

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  • dc.contributor.author Boix, Olga
  • dc.contributor.author Albà Soler, Mar
  • dc.contributor.author Abad, María
  • dc.date.accessioned 2023-04-19T11:41:32Z
  • dc.date.available 2023-04-19T11:41:32Z
  • dc.date.issued 2022
  • dc.description.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.
  • dc.description.sponsorship The authors thank VHIO Proteomics, Molecular Oncology and Genomics Core Facilities for technical assistance. We are grateful to Manuel Serrano for providing several reagents, advice and critical discussion on the manuscript. We also thank Alonso García and Raquel Pérez for their help in processing and analyzing digital images, Gemma Serra and Sandra Peiró for their assistance with subcellular fractionation and immunoprecipitation experiments, Sara Arce and Joaquín Mateo for providing several reagents during the development of critical experiments of this manuscript, and Juan Angel Recio for his help with the cSCC cohort. We are immensely grateful to all the members of the Abad lab for generating the know-how for the identification of novel sORFs, for the critical reading on the manuscript and in general for their constant support to this project. Work in the Abad lab is supported by VHIO, Fero Foundation, La Caixa Foundation, Asociación Española Contra el Cancer (AECC), La Mutua Foundation and by grants from the Spanish Ministry of Science and Innovation (SAF2015-69413-R; RTI2018-102046-B-I00). M.A. was recipient of a Ramón y Cajal contract from the Spanish Ministry of Science and Innovation (RYC-2013-14747). O.B. is recipient of a FPI-AGAUR fellowship from Generalitat de Catalunya. We also acknowledge funding from grant PGC2018-094091-B-I00 from the Spanish Government.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Boix O, Martinez M, Vidal S, Giménez-Alejandre M, Palenzuela L, Lorenzo-Sanz L, et al. 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
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-022-34529-6
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/56501
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2022 Nov 11;13(1):6840
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69413-R
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-102046-B-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PGC2018-094091-B-I00
  • dc.rights © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer
  • dc.subject.keyword Mechanisms of disease
  • dc.title pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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