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

Olga Boix, Marion Martinez, Santiago Vidal, Marta Giménez-Alejandre, Lluís Palenzuela, Laura Lorenzo-Sanz, Laura Quevedo, Olivier Moscoso, Jorge Ruiz-Orera, Pilar Ximénez-Embún, Nikaoly Ciriaco, Paolo Nuciforo, Camille Stephan-Otto Attolini, M. Mar Albà, Javier Muñoz, Tian V. Tian, Ignacio Varela, Ana Vivancos, Santiago Ramón y Cajal, Purificación Muñoz, Carmen Rivas and María Abad ()
Additional contact information
Olga Boix: Vall d’Hebron Institute of Oncology (VHIO)
Marion Martinez: Vall d’Hebron Institute of Oncology (VHIO)
Santiago Vidal: Universidad de Santiago de Compostela and Instituto de Investigaciones Sanitarias (IDIS)
Marta Giménez-Alejandre: Vall d’Hebron Institute of Oncology (VHIO)
Lluís Palenzuela: Vall d’Hebron Institute of Oncology (VHIO)
Laura Lorenzo-Sanz: Bellvitge Biomedical Research Institute (IDIBELL)
Laura Quevedo: Universidad de Cantabria - CSIC
Olivier Moscoso: Universitat Autònoma de Barcelona and Spanish Biomedical Research Network Centre in Oncology (CIBERONC)
Jorge Ruiz-Orera: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Pilar Ximénez-Embún: Spanish National Cancer Research Centre (CNIO)
Nikaoly Ciriaco: Universitat Autònoma de Barcelona and Spanish Biomedical Research Network Centre in Oncology (CIBERONC)
Paolo Nuciforo: Vall d’Hebron Institute of Oncology (VHIO)
Camille Stephan-Otto Attolini: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST)
M. Mar Albà: IMIM - Hospital del Mar Medical Research Institute
Javier Muñoz: Spanish National Cancer Research Centre (CNIO)
Tian V. Tian: Vall d’Hebron Institute of Oncology (VHIO)
Ignacio Varela: Universidad de Cantabria - CSIC
Ana Vivancos: Vall d’Hebron Institute of Oncology (VHIO)
Santiago Ramón y Cajal: Universitat Autònoma de Barcelona and Spanish Biomedical Research Network Centre in Oncology (CIBERONC)
Purificación Muñoz: Bellvitge Biomedical Research Institute (IDIBELL)
Carmen Rivas: Universidad de Santiago de Compostela and Instituto de Investigaciones Sanitarias (IDIS)
María Abad: Vall d’Hebron Institute of Oncology (VHIO)

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34529-6

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