HMGB1 and HMGB2 Interactomes in Ovarian and Prostate Tumours

Abstract

The HMGB family of proteins includes nuclear proteins with the ability to bind DNA and participate in transcriptional regulation and DNA repair processes, as well as to respond to cellular oxidative damage. The main objective of this work aims to identify new physical interactions of the HMGB1 and HMGB2 proteins with other proteins in ovarian and prostate tumours. The identification of new physical interactions of these proteins would allow a better understanding of their mechanism of action and their role in cancer-related signaling pathways. Through experimental approaches based on the double hybrid, proteomic studies have been carried out using cDNA libraries prepared from isolated ovarian and prostate tumours from patients. The functionality of the interactions found has also been validated by bioinformatic meta-analyses of other data collected in databases on their expression levels and association with clinical survival parameters. Two selected interactions have also been validated by co-immunoprecipitation and by cell localization using confocal microscopy from cancer cells in culture. Some functional characteristics of HMGB1 and HMGB2 proteins, as well as NOP53 and MIEN1, detected in this study as new proteins of physical interaction with HMGB proteins have been analyzed in greater detail. The effects produced by its silencing and the variation in expression levels in reaction to external treatments with compounds used in chemotherapy such as carboplatin, paclitaxel, olaparib and bevacizumab were analyzed. In addition, the HMGB1, HMGB2, NOP53 and MIEN1 proteins, together with the miRNAs miR-155, miR-124 and miR-146a, were detected in extracellular vesicles (EV) derived from prostate cell lines, and variations were observed after treatment with temozolomide (TMZ) or a new hybrid compound based on TMZ and valproic acid (1D). This study is the basis for the search for new biomarkers or therapeutic targets useful to overcome resistance to anti-tumour drugs currently used in these types of cancer.