The Effect of HMGB1 and HMGB2 on Transcriptional Regulation Differs in Neuroendocrine and Adenocarcinoma Models of Prostate Cancer

TL;DR

This study shows that HMGB1 and HMGB2 proteins regulate gene expression differently in aggressive and non-aggressive prostate cancer models.

Contribution

The study reveals distinct regulatory roles of HMGB1 and HMGB2 in neuroendocrine versus adenocarcinoma prostate cancer models.

Findings

HMGB1 mainly repressed gene expression, while HMGB2 activated it in prostate cancer cells.

Genes like SERPINE1, CDK1, and ZWINT showed significant expression changes after HMGB1 or HMGB2 manipulation.

Differences in HMGB1 and HMGB2 regulation were observed between neuroendocrine and adenocarcinoma prostate cancer subtypes.

Abstract

Human high-mobility group-B (HMGB) proteins regulate gene expression in prostate cancer (PCa), a leading cause of oncological death in men. Their role in aggressive PCa cancers, which do not respond to hormonal treatment, was analyzed. The effects of HMGB1 and HMGB2 silencing upon the expression of genes previously related to PCa were studied in the PCa cell line PC-3 (selected as a small cell neuroendocrine carcinoma, SCNC, PCa model not responding to hormonal treatment). A total of 72% of genes analyzed, using pre-designed primer panels, were affected. HMGB1 behaved mostly as a repressor, but HMGB2 as an activator. Changes in SERPINE1, CDK1, ZWINT, and FN1 expression were validated using qRT-PCR after HMGB1 silencing or overexpression in PC-3 and LNCaP (selected as an adenocarcinoma model of PCa responding to hormonal treatment) cell lines. Similarly, the regulatory role of HMGB2 upon SERPINE1, ZWINT, FN1, IGFPB3, and TYMS expression was validated, finding differences between cell lines. The correlation between the expression of HMGB1, HMGB2, and their targets was analyzed in PCa patient samples and also in PCa subgroups, classified as neuroendocrine positive or negative, in public databases. These results allow a better understanding of the role of HMGB proteins in PCa and contribute to find specific biomarkers for aggressive PCa.

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