A new horizon in oncology: SUMOylation and its determining role in the evolution of hepatic cancer

The complexity and heterogeneity of hepatocellular carcinoma (HCC) are well-known. Despite advancements in systemic therapies, achieving comparable progress to other cancers remains elusive. This study, published in the prestigious journal Cell Reports, reveal new therapeutic possibilities by demonstrating that SUMOylation of specific proteins, such as HuR, plays an essential role in the progression of liver carcinoma.

The Hepatic Diseases Laboratory, led by Dr. Malu Martínez-Chantar at CIC bioGUNE – member of BRTA– and CIBEREHD, made a groundbreaking contribution to the field of oncology with its latest publication in the international journal Cell Reports.

This pivotal study unveils previously undiscovered molecular mechanisms that are instrumental in the progression from healthy hepatic tissue to hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer.

The research underscores the significance of post-translational protein modifications through SUMOylation, an evolutionary conserved process in eukaryotes that enhances the structural and functional diversity of the proteome. This novel finding sheds light on cutting-edge therapeutic avenues by demonstrating the critical role of protein SUMOylation, particularly of HuR, in the progression of hepatic carcinoma.

HCC is notorious for its extensive heterogeneity and intricacy. Despite current treatments, including first and second-line systemic therapies, leading to increased patient survival rates, they have not achieved the substantial progress seen in other cancers. Accordingly, this study advocates for the pursuit of combined therapeutic strategies and the identification of new therapeutic targets in HCC, emphasizing the therapeutic potential of SUMOylation and its influence on critical nuclear processes like transcription, DNA damage response, and cell cycle regulation.

The study reveals that SUMOylation of HuR, a protein implicated in the post-transcriptional regulation of multiple genes, fosters cancer hallmarks such as proliferation and invasion. Conversely, the absence of HuR SUMOylation induces a senescent phenotype, triggering structural and functional damage in mitochondria and the endoplasmic reticulum. These findings accentuate the importance of post-translational modifications as therapeutic targets and pave the way for combined strategies in HCC treatment.

This advancement not only broadens our understanding of the role of SUMOylation in hepatic carcinogenesis but also points to a hopeful therapeutic approach for the development of targeted treatments that could revolutionize the clinical management of liver cancer. Dr. Malu Martínez Chantar's Hepatic Diseases Laboratory at CIC bioGUNE continues to spearhead cancer research, dedicated to discovering innovative solutions for this devastating disease.

The lead authors of the paper, Sofia Lachiondo and Dr. Claudia Rejano, assert that identifying HuR SUMOylation in liver cancer patients brings these findings closer to clinical application. The research was conducted in collaboration with various national and international institutions and hospitals.

Reference: Sofia Lachiondo-Ortega, Claudia M. Rejano-Gordillo, Jorge Simon, Fernando Lopitz-Otsoa, Teresa C. Delgado, Krystyna Mazan-Mamczarz, Naroa Goikoetxea-Usandizaga, L. Estefanía Zapata-Pavas, Ana García-del Río, Pietro Guerra, Patricia Peña-Sanfélix, Natalia Hermán-Sánchez, Ruba Al-Abdulla, Carmen Fernandez-Rodríguez, Mikel Azkargorta, Alejandro Velázquez-Cruz, Joris Guyon, César Martín, Juan Diego Zalamea, Leire Egia-Mendikute, Arantza Sanz-Parra, Marina Serrano-Maciá, Irene González-Recio, Monika Gonzalez-Lopez, Luis Alfonso Martínez-Cruz, Patrizia Pontisso, Ana M. Aransay, Rosa Barrio, James D. Sutherland, Nicola G.A. Abrescia, Félix Elortza, Amaia Lujambio, Jesus M. Banales, Raúl M. Luque, Manuel D. Gahete, Asís Palazón, Matias A. Avila, Jose J. G. Marin, Supriyo De, Thomas Daubon, Antonio Díaz-Quintana, Irene Díaz-Moreno, Myriam Gorospe, Manuel S. Rodríguez, María Luz Martínez-Chantar. Cell Reports. DOI: 10.1016/j.celrep.2024.113924.

About CIBEREHD

The Consortium of Biomedical Network Research Centers (CIBER) is a public research consortium created on the initiative of the Instituto de Salud Carlos III / Carlos III Health Institute, of the Ministry of Science and Innovation, to further research of excellence in biomedicine and health sciences conducted within the National Health System and the Science and Technology System. The scientific program of the CIBER is organized around 13 thematic areas of research, including the area of Liver and Digestive Diseases (CIBEREHD).

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About BRTA

BRTA is an alliance of 4 collaborative research centres (CIC bioGUNE, CIC nanoGUNE, CIC biomaGUNE y CIC energiGUNE) and 13 technology centres (Azterlan, Azti, Ceit, Cidetec, Gaiker, Ideko, Ikerlan, Leartiker, Lortek, Neiker, Tecnalia, Tekniker and Vicomtech) with the main objective of developing advanced technological solutions for the Basque corporate fabric.

With the support of the Basque Government, the SPRI Group and the Provincial Councils of the three territories, the alliance seeks to promote collaboration between the research centres, strengthen the conditions to generate and transfer knowledge to companies, contributing to their competitiveness and outspreading the Basque scientific-technological capacity abroad.

BRTA has a workforce of 3,500 professionals, executes 22% of the Basque Country's R&D investment, registers an annual turnover of more than 300 million euros and generates 100 European and international patents per year.