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Abstract
High mobility group box B (HMGB) proteins are pivotal in the development of cancer. Although the proteomics of prostate cancer (PCa) cells has been reported, the involvement of HMGB proteins and their interactome in PCa is an unexplored field of considerable interest. We describe herein the results of the first HMGB1/HMGB2 interactome approach to PCa. Libraries constructed from the PCa cell line, PC-3, and from patients’ PCa primary tumor have been screened by the yeast 2-hybrid approach (Y2H) using HMGB1 and HMGB2 baits. Functional significance of this PCa HMGB interactome has been validated through expression and prognosis data available on public databases. Copy number alterations (CNA) affecting these newly described HMGB interactome components are more frequent in the most aggressive forms of PCa: those of neuroendocrine origin or castration-resistant PCa. Concordantly, adenocarcinoma PCa samples showing CNA in these genes are also associated with the worse prognosis. These findings open the way to their potential use as discriminatory biomarkers between high and low risk patients. Gene expression of a selected set of these interactome components has been analyzed by qPCR after HMGB1 and HMGB2 silencing. The data show that HMGB1 and HMGB2 control the expression of several of their interactome partners, which might contribute to the orchestrated action of these proteins in PCa
Highlights
Human high mobility group box B (HMGB) proteins HMGB1, 2, and 3 are differentially expressed in many different tissues and cell types, whereas HMGB4 expression is restricted to the testis [1]
Hormonal inhibition of androgen receptor (AR) signaling is the therapeutic choice for patients with adenocarcinomas, but the disease usually progresses as it becomes independent of exogenous AR induction, leading to castration-resistant prostate cancer (CRPC) with a worse prognosis
HMGB2 have not previously been reported on Biogrid, String, or other public databases, we have previously reported that Cytokeratin-7, the human complement subcomponent C1q (C1QPB), and zinc finger p rotein 428 (ZNF428) interact with HMGB1 and that (high density lipoprotein-binding protein (HDLBP) and ZNF428 interact with HMGB2 in noncancerous epithelial cells [26]
Summary
Human high mobility group box B (HMGB) proteins HMGB1, 2, and 3 are differentially expressed in many different tissues and cell types, whereas HMGB4 expression is restricted to the testis [1]. HMGB1 has been related to the onset and progression of cancer, being involved in events such as replenishing telomeric DNA and maintaining cell immortality [6], autophagic increase, evasion of apoptosis [7,8], as well as cell proliferation and invasion [9,10]. The role of HMGB2 in these processes, less well studied, has been related to cell viability and invasion [14], EMT [10], and angiogenesis [15]. Hormonal inhibition of AR signaling is the therapeutic choice for patients with adenocarcinomas, but the disease usually progresses as it becomes independent of exogenous AR induction, leading to castration-resistant prostate cancer (CRPC) with a worse prognosis.
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