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

• DOI: 10.1038/s41467-022-34529-6
• Publication Date: 2022-11-11T14:03:22Z
• Authors: Olga Boix; Marion Martinez; Santiago Vidal; Marta Giménez-Ale...; Lluís Palenzuela; Laura Lorenzo-Sanz; Laura Quevedo; Olivier Moscoso; Jorge Ruiz-Orera; Pilar Ximénez-Embún; Nikaoly Ciriaco; Paolo Nuciforo; Camille Stephan-O...; M. Mar Albà; Javier Muñoz; Tian V. Tian; Ignacio Varela; Ana Vivancos; Santiago Ramón y ...; Purificación Muñoz; Carmen Rivas; María Abad
• Keywords: CDC42

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