The text provides a comprehensive overview of the role of BRPF1 (bromodomain and PHD finger-containing protein 1) in various gastrointestinal cancers and other cancer types. Here’s a detailed summary and analysis of the key points related to BRPF1’s function:
Role of BRPF1 in Gastrointestinal Cancers
Hepatocellular Carcinoma (LIHC)
- Oncogenic Function: BRPF1 acts as an oncogene in liver cancer (LIHC), with increased expression linked to tumor progression.
- Regulation: Overexpression may be driven by transcription factors such as SP1 and mutant p53 variants (e.g., p53R249S, p53Y220C), which bind BRPF1 regulatory elements, promoting chromatin remodeling and histone acetylation.
- Environmental Influence: Exposure to environmental toxins like endosulfan induces BRPF1, while inflammation-related cytokine NFα decreases its expression.
- Prognostic Marker: Elevated BRPF1 correlates with poor overall and disease-free survival, and its expression is positively associated with proliferation markers (Ki67) and other oncogenic factors (MOZ, MORF, MTA2).
- Cancer Stemness: BRPF1 is upregulated in liver cancer stem cells (CD133+), maintaining stemness via regulation of NOTCH1, OCT4, and EPCAM.
- Mechanism: Regulates oncogenes E2F2 and EZH2 by modulating MOZ/MORF acetyltransferase activity and H3K14 acetylation.
- Therapeutic Targeting: Genetic knockout or pharmacological inhibition (e.g., GSK5959, OF-1, NI-57) reduces tumor growth, inducing senescence and cell cycle arrest.
Colon Adenocarcinoma (COAD)
- BRPF1 upregulation driven by Pygo2, a Wnt/β-catenin coactivator.
- BRPF1 promotes proliferation and stem-like properties.
- Targeting BRPF1 reduces colony formation and tumor growth in Pygo2-high cells.
Gastrointestinal Stromal Tumor (GIST)
- BRPF1 identified as essential in genome-wide CRISPR-Cas9 screens.
- Pharmacological inhibition results were inconsistent regarding cell proliferation, possibly due to low drug doses.
Esophageal Cancer (ESCA)
- BRPF1 promoter shows an active chromatin state in cfDNA from ESCA patients, suggesting a potential diagnostic/prognostic marker function.
Role of BRPF1 in Genitourinary Tumors
Prostate Cancer (PCa)
- Expression inversely reported but increased BRPF1 associates with progression parameters (Gleason score, stage, recurrence risk).
- BRPF1 stabilizes through USP35-mediated deubiquitination, enhancing transcription of SREBP2, which drives mevalonate metabolism.
- Contributes to taxane resistance by regulating ABCB1-mediated drug efflux and cell cycle progression.
- BRPF1 inhibition reverses resistance and synergizes with chemotherapy.
Ovarian Cancer (OC)
- Genomic amplifications and aberrant cytoplasmic localization via fucosylation noted; mRNA-protein expression discrepancies exist.
- High BRPF1 correlates with poor outcomes and advanced disease.
- Promotes proliferation, anaerobic metabolism, and Wnt signaling.
- Knockdown induces apoptosis, cell cycle disruption, and DNA damage.
- Involved in immune modulation, affecting immune checkpoint expression and immune infiltration.
- Pharmacological inhibition impacts lipid metabolism and inflammatory pathways.
- BRPF1 is part of key gene signatures predicting prognosis.
Role of BRPF1 in Brain Cancers
- Elevated in high-grade gliomas, where inhibition reduces proliferation.
- Involved in adult Sonic hedgehog medulloblastoma with mutations contributing to tumorigenesis, potentially independent of SMO mutations.
- BRPF1 mutations promote neuronal dedifferentiation and tumor formation.
Role of BRPF1 in Skin Cancers
- Overexpressed in melanoma at both mRNA and protein levels.
- Combined pharmacological inhibition with CDC7 inhibitor impacts tumor cell survival pathways (MYC, IGF1R) and induces apoptosis and cell cycle arrest.
Summary of Mechanisms & Therapeutic Implications
- Chromatin Remodeling and Histone Acetylation: BRPF1 modulates acetyltransferase activity (MOZ/MORF complexes) influencing transcription of oncogenes and pathways crucial for cell cycle progression and stemness.
- Cancer Stem Cell Maintenance: BRPF1 sustains stem-like cell populations, which are critical for tumor propagation and resistance.
- Metabolism and Drug Resistance: Especially in prostate cancer, BRPF1 influences metabolic pathways and chemoresistance mechanisms.
- Therapeutic Target: Pharmacological inhibitors of BRPF1 (e.g., GSK5959, OF-1, NI-57) show promise by arresting the cell cycle, inducing apoptosis, and reducing tumor growth both in vitro and in vivo.
- Diagnostic and Prognostic Biomarker: BRPF1 expression correlates with progression, stage, and survival in multiple cancers, making it a candidate biomarker.
In conclusion, BRPF1 is a multifaceted epigenetic regulator with oncogenic roles in gastrointestinal, genitourinary, brain, and skin cancers. It influences key pathways related to chromatin remodeling, metabolism, stemness, and drug resistance, positioning it as a valuable diagnostic marker and therapeutic target.
