PhD Scientific Days 2024

Budapest, 9-10 July 2024

Poster Session A - Molecular Medicine 1.

Understanding HAUSP and SUMO Interplay as a Therapeutical Approach for Hepatocellular Carcinoma

Author(s)

Beatriz Rodríguez-Lemus1,2, Rocío M. Tolosa1,2, Maria Blanquer1,2, Carmen Rivas1,2,3
1: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain
2: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS),15782, Santiago de Compostela, Spain
3: Cellular and Molecular Biology, Centro Nacional de Biotecnología (CNB-CSIC), 28049, Madrid, Spain

Text of the abstract

Introduction

Herpesvirus associated ubiquitin-specific protease (HAUSP/USP7) is a deubiquitinase that regulates numerous substrates and is involved in the regulation of essential cellular processes such as cell cycle or DNA repair. An alteration in its activity is related to different types of cancer including hepatocellular carcinoma (HCC). Identification of the molecular mechanisms involved in the regulation of HAUSP is key to control its activity. One of the molecular pathways that modulates the levels and activity of numerous proteins is the small ubiquitin-like protein (SUMO) conjugation pathway. Current evidence show a correlation between upregulation in global SUMOylation and tumour progression and metastasis in HCC. These results and the importance of HAUSP in HCC lead us to propose the hypothesis that the modulation of HAUSP-SUMO interaction may be a therapeutic strategy in HCC treatment.

Aims

The principal objective of this work is to understand the molecular interplay between HAUSP and SUMO and to decipher its impact on tumour progression, specifically in hepatocellular carcinoma.

Method

Interplay between HAUSP and SUMO is being evaluated using immunofluorescence assay, pull-down assay, co-immunoprecipitations, or in vitro and in vivo SUMOylation assays. To decipher its impact on tumour progression we first need to generate a SUMOylation mutant for HAUSP and to evaluate the impact of this mutation in HAUSP functions. Then, we need to modulate the HAUSP-SUMO interaction in a HCC model and to evaluate the effect of this modulation on cellular proliferation, apoptosis, migration, metastasis, etc.

Results

Results of our lab reveal the covalent conjugation of HAUSP to SUMO. Moreover, we have preliminary data indicating that HAUSP also interacts with SUMO in a non-covalent manner. Finally, our results point to the HAUSP domains involved in SUMO interaction.


Conclusions
Our results, so far, indicate that SUMO interacts and modulate HAUSP. This interaction may be a therapeutic strategy against those HAUSP-related diseases


Funding

Ayuda predoctoral 2024 from Asociación Española Contra el Cáncer; Proteínas tipo ubiquitina en la interacción virus-célula. PID2021-126510NB-100, Ministerio de Ciencia e Innovación. PI: Carmen Rivas.