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Published on: July 28, 2010
BRD4-S Drives Colorectal Cancer Progression via DDX27-Regulated Splicing and MAPK Signaling Activation
Chenlu Wang1, Hong Hong2, Lining Zhou1
1Department of Laboratory Medicine, The Second Affiliated Hospital of Nantong University and Nantong First People's Hospital, 226001 Nantong, Jiangsu, China.
Background:
As a major contributor to cancer-associated deaths, advanced colorectal cancer (CRC) has a constrained range of effective treatment options. The short isoform of bromodomain-containing protein 4 (BRD4-S) has recently been implicated as a potential oncogenic driver; however, its regulatory mechanisms and functional role in CRC remain incompletely understood.
Methods:
BRD4-S expression, regulation, and function in CRC were investigated through bioinformatics analyses of the Cancer Genome Atlas (TCGA) datasets, in vitro studies using CRC cell lines (HT29, SW620), and in vivo xenograft models in nude mice. Experimental approaches included quantitative real-time PCR (qRT-PCR), Western blotting, co-immunoprecipitation, RNA immunoprecipitation, immunofluorescence, colony formation, Cell Counting Kit-8 (CCK-8), and scratch assays. Gene enrichment and interaction analyses were performed to identify relevant pathways and molecular partners.
Results:
BRD4-S was markedly upregulated in CRC tissues and cell lines, and elevated BRD4-S expression correlated with poorer patient survival. Silencing BRD4-S, but not BRD4-L, significantly impaired CRC cell proliferation, migration, and tumor growth in vivo. Mechanistically, the RNA helicase DEAD-box helicase 27 (DDX27) interacted with Serine and Arginine Rich Splicing Factor 6 (SRSF6) to promote alternative splicing of BRD4 pre-mRNA toward the BRD4-S isoform. Inhibition of SRSF6 phosphorylation suppressed BRD4-S production and blocked activation of the mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinases ERK signaling pathway, identified as a key downstream effector of BRD4-S.
Conclusions:
This study defines a novel DDX27-SRSF6-BRD4-S-MAPK/ERK signaling axis that drives CRC progression. These findings underscore the therapeutic potential of targeting BRD4 isoform switching and its regulatory splicing machinery in CRC.
Insights
Advanced colorectal cancer (CRC) is driven by the short isoform of bromodomain-containing protein 4 (BRD4-S). Targeting the DDX27-SRSF6-BRD4-S-MAPK/ERK pathway offers new therapeutic strategies for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Advanced colorectal cancer (CRC) presents limited treatment options and significant mortality.
- The short isoform of bromodomain-containing protein 4 (BRD4-S) is a potential oncogenic driver in CRC, but its regulation and function are unclear.
Purpose of the Study:
- To investigate the regulatory mechanisms and functional role of BRD4-S in colorectal cancer progression.
- To identify potential therapeutic targets within the BRD4-S regulatory pathway.
Main Methods:
- Bioinformatics analysis of TCGA datasets, in vitro studies with CRC cell lines, and in vivo xenograft models.
- Quantitative PCR, Western blotting, co-immunoprecipitation, RNA immunoprecipitation, and cell-based assays were employed.
- Gene enrichment and interaction analyses identified key pathways and molecular partners.
Main Results:
- BRD4-S was significantly upregulated in CRC tissues and correlated with poor patient survival.
- Silencing BRD4-S inhibited CRC cell proliferation, migration, and tumor growth.
- DDX27 and SRSF6 interaction promotes BRD4-S splicing, activating the MAPK/ERK pathway.
Conclusions:
- A novel DDX27-SRSF6-BRD4-S-MAPK/ERK signaling axis drives CRC progression.
- Targeting BRD4 isoform switching and its splicing machinery holds therapeutic potential for CRC.
