HMGB1 Protein Interactions in Prostate and Ovary Cancer Models Reveal Links to RNA Processing and Ribosome Biogenesis
Aida Barreiro-Alonso1,2,3,4, Mónica Lamas-Maceiras1,2,3, Lidia Lorenzo-Catoira1,2,3
1EXPRELA Group, Centro de Investigaciones Científicas Avanzadas (CICA), University of A Coruña (UDC), 15008 A Coruña, Spain.
Abstract:
This study reports the HMGB1 interactomes in prostate and ovary cancer cells lines. Affinity purification coupled to mass spectrometry confirmed that the HMGB1 nuclear interactome is involved in HMGB1 known functions such as maintenance of chromatin stability and regulation of transcription, and also in not as yet reported processes such as mRNA and rRNA processing. We have identified an interaction between HMGB1 and the NuRD complex and validated this by yeast-two-hybrid, confirming that the RBBP7 subunit directly interacts with HMGB1. In addition, we describe for the first time an interaction between two HMGB1 interacting complexes, the septin and THOC complexes, as well as an interaction of these two complexes with Rab11. Analysis of Pan-Cancer Atlas public data indicated that several genes encoding HMGB1-interacting proteins identified in this study are dysregulated in tumours from patients diagnosed with ovary and prostate carcinomas. In PC-3 cells, silencing of HMGB1 leads to downregulation of the expression of key regulators of ribosome biogenesis and RNA processing, namely BOP1, RSS1, UBF1, KRR1 and LYAR. Upregulation of these genes in prostate adenocarcinomas is correlated with worse prognosis, reinforcing their functional significance in cancer progression.
Insights
High-mobility group box 1 (HMGB1) interacts with proteins involved in chromatin stability, transcription, and RNA processing in cancer cells. These HMGB1 interactions are dysregulated in ovarian and prostate tumors, impacting cancer progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Proteomics
Background:
- High-mobility group box 1 (HMGB1) is a nuclear protein with established roles in chromatin stability and transcription.
- The full spectrum of HMGB1 interactions and their functional implications in cancer remain incompletely understood.
Purpose of the Study:
- To identify and characterize the HMGB1 interactome in prostate and ovary cancer cell lines.
- To investigate the functional significance of HMGB1 interactions in cancer progression.
Main Methods:
- Affinity purification coupled with mass spectrometry (AP-MS) to identify HMGB1 interacting proteins.
- Yeast-two-hybrid assays to validate specific protein-protein interactions.
- Analysis of Pan-Cancer Atlas data to correlate gene expression with clinical outcomes.
Main Results:
- The HMGB1 nuclear interactome includes proteins involved in chromatin stability, transcription, and novel roles in mRNA and rRNA processing.
- Identified interactions between HMGB1 and the NuRD complex (specifically RBBP7), and between the septin and THOC complexes with Rab11.
- Dysregulation of genes encoding HMGB1-interacting proteins in ovarian and prostate carcinomas was observed.
- Silencing HMGB1 in PC-3 cells downregulated key regulators of ribosome biogenesis and RNA processing (BOP1, RSS1, UBF1, KRR1, LYAR).
Conclusions:
- HMGB1 plays a significant role in RNA processing, beyond its known functions in chromatin and transcription.
- Novel HMGB1 interaction networks involving the NuRD, septin, THOC, and Rab11 complexes were elucidated.
- The identified HMGB1-interacting proteins and their dysregulation in cancer highlight potential therapeutic targets and prognostic markers for prostate and ovarian carcinomas.
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