The TINCR ubiquitin-like microprotein is a tumor suppressor in squamous cell carcinoma

Lucia Morgado-Palacin, Jessie A. Brown, Thomas F. Martinez, Juana M. Garcia-Pedrero, Farhad Forouhar, S. Aidan Quinn, Clara Reglero, Joan Vaughan, Yasamin Hajy Heydary, Cynthia Donaldson, Sandra Rodriguez-Perales, Eva Allonca, Rocio Granda-Diaz, Agustin F. Fernandez, Mario F. Fraga, Arianna L. Kim, Jorge Santos-Juanes, David M. Owens, Juan P. Rodrigo, Alan Saghatelian and Adolfo A. Ferrando ()
Additional contact information
Lucia Morgado-Palacin: Columbia University
Jessie A. Brown: Columbia University
Thomas F. Martinez: University of California
Juana M. Garcia-Pedrero: Hospital Universitario Central de Asturias (HUCA)
Farhad Forouhar: Columbia University
S. Aidan Quinn: Columbia University
Clara Reglero: Columbia University
Joan Vaughan: Salk Institute for Biological Studies
Yasamin Hajy Heydary: University of California
Cynthia Donaldson: Salk Institute for Biological Studies
Sandra Rodriguez-Perales: Centro Nacional de Investigaciones Oncológicas (CNIO)
Eva Allonca: Hospital Universitario Central de Asturias (HUCA)
Rocio Granda-Diaz: Hospital Universitario Central de Asturias (HUCA)
Agustin F. Fernandez: Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
Mario F. Fraga: Instituto de Investigación Sanitaria del Principado de Asturias (ISPA)
Arianna L. Kim: Columbia University Irving Medical Center
Jorge Santos-Juanes: Hospital Universitario Central de Asturias (HUCA)
David M. Owens: Columbia University Irving Medical Center
Juan P. Rodrigo: Hospital Universitario Central de Asturias (HUCA)
Alan Saghatelian: Salk Institute for Biological Studies
Adolfo A. Ferrando: Columbia University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract The TINCR (Terminal differentiation-Induced Non-Coding RNA) gene is selectively expressed in epithelium tissues and is involved in the control of human epidermal differentiation and wound healing. Despite its initial report as a long non-coding RNA, the TINCR locus codes for a highly conserved ubiquitin-like microprotein associated with keratinocyte differentiation. Here we report the identification of TINCR as a tumor suppressor in squamous cell carcinoma (SCC). TINCR is upregulated by UV-induced DNA damage in a TP53-dependent manner in human keratinocytes. Decreased TINCR protein expression is prevalently found in skin and head and neck squamous cell tumors and TINCR expression suppresses the growth of SCC cells in vitro and in vivo. Consistently, Tincr knockout mice show accelerated tumor development following UVB skin carcinogenesis and increased penetrance of invasive SCCs. Finally, genetic analyses identify loss-of-function mutations and deletions encompassing the TINCR gene in SCC clinical samples supporting a tumor suppressor role in human cancer. Altogether, these results demonstrate a role for TINCR as protein coding tumor suppressor gene recurrently lost in squamous cell carcinomas.

Date: 2023
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DOI: 10.1038/s41467-023-36713-8

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