SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

Sofia Lachiondo-Ortega (1, 2) , Claudia M Rejano-Gordillo (1, 2, 3, 4) , Jorge Simon (1, 5) , Fernando Lopitz-Otsoa (1) , Teresa C. Delgado (1) , Krystyna Mazan-Mamczarz , Naroa Goikoetxea-Usandizaga (1) , L. Estefanía Zapata-Pavas (1) , Ana García-del Río (1) , Pietro Guerra (6) , Patricia Peña-Sanfélix (1) , Natalia Hermán-Sánchez (7) , Ruba Al-Abdulla (8, 9) , Carmen Fernandez-Rodríguez (1) , Mikel Azkargorta (5, 10) , Alejandro Velázquez-Cruz (11) , Joris Guyon (12, 13) , César Martín (14) , Juan Diego Zalamea (1) , Leire Egia-Mendikute (1) , Arantza Sanz-Parra (1) , Marina Serrano-Maciá (1) , Irene González-Recio (1) , Monika Gonzalez-Lopez (1) , Luis Alfonso Martínez-Cruz (1) , Patrizia Pontisso (6) , Ana M Aransay (1) , Rosa Barrio (1) , James D Sutherland (1) , Nicola G A Abrescia (1, 15) , Félix Elortza (5) , Amaia Lujambio (16) , Jesus M Banales (5, 15, 10, 17) , Raúl M Luque (7) , Manuel D Gahete (7) , Asís Palazón (1, 15) , Matias A Avila (5, 18, 19) , Jose J G. Marin (5, 20) , Supriyo De , Thomas Daubon (21) , Antonio Díaz-Quintana (11) , Irene Díaz-Moreno (11) , Myriam Gorospe , Manuel S Rodriguez (22) , María Luz Martínez-Chantar (5)

1 CIC bioGUNE - Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne)
2 BRTA - Basque Research and Technology Alliance
3 UEX - Universidad de Extremadura - University of Extremadura
4 Biofisika Institute (CSIC, UPV/EHU), 48940 Leioa,
5 CIBERehd - Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas
6 Unipd - Università degli Studi di Padova = University of Padua
7 IMIBIC - Instituto Maimonides de Investigación Biomédica de Cordoba
8 UMH - Universidad Miguel Hernández [Elche]
9 University of Medicine Greifswald
10 UPNA - Universidad Pública de Navarra [Espagne] = Public University of Navarra
11 Scientific Research Centre 'Isla de la Cartuja' (cicCartuja)
12 BPH - Bordeaux population health
13 CHU de Bordeaux - Centre Hospitalier Universitaire de Bordeaux
14 UPV/EHU - Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne]
15 Ikerbasque - Basque Foundation for Science
16 MSSM - Icahn School of Medicine at Mount Sinai [New York]
17 BIODonostia Research Institute
18 CIMA - Center for Applied Medical Research [Plamplona]
19 IdiSNA - Navarra Institute for Health Research / Instituto de Investigación Sanitaria de Navarra
20 IBSAL - Instituto de Investigación Biomédica de Salamanca
21 IBGC - Institut de biochimie et génétique cellulaires
22 LCC - Laboratoire de chimie de coordination

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Mots clés: ELAVL1; SUMO; PTMs; Senescence; HCC

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Hépatologie et Gastroentérologie

Sofia Lachiondo-Ortega, Claudia M Rejano-Gordillo, Jorge Simon, Fernando Lopitz-Otsoa, Teresa C. Delgado, et al.. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer. Cell Reports, 2024, 43 (3), pp.113924. ⟨10.1016/j.celrep.2024.113924⟩. ⟨hal-04522023⟩