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GLTSCR1 Negatively Regulates BRD4-Dependent Transcription Elongation and Inhibits CRC Metastasis
Fengyan Han1, Lei Zhang2, Chaoyi Chen1
1Department of Pathology Key Laboratory of Disease Proteomics of Zhejiang Province Research unit of intelligence classification of tumor pathology and precision therapy Chinese Academy of Medical Sciences (2019RU042) School of Medicine Zhejiang University Hangzhou 310058 China.
Abstract:
Frameshift mutations frequently occur in colorectal cancer (CRC) with microsatellite instability (MSI), but the nature and biological function of many MSI-associated mutations remain elusive. Here, an MSI frameshift mutation is identified in glioma tumor suppressor candidate region gene 1 (GLTSCR1) that produces two C-terminal-truncated proteins. Additionally, GLTSCR1 is verified as a tumor suppressor that inhibits CRC metastasis. Through binding to bromodomains and the phosphorylation-dependent interaction domain of bromodomain protein 4 (BRD4) via the C-terminus, GLTSCR1 blocks oncogenic transcriptional elongation. However, truncated GLTSCR1 translocates into the cytoplasm and loses BRD4 binding domain, which induces the phosphorylation of RNA Pol II at Ser2 and dephosphorylation at Ser5, then increases oncogenic transcriptional elongation. Importantly, GLTSCR1 deficiency decreases sensitivity to bromodomain and extra terminal domain inhibitors. This study highlights the molecular mechanism of the GLTSCR1-BRD4 interaction, which is a potential therapeutic target for CRC.
Insights
Microsatellite instability in colorectal cancer (CRC) causes frameshift mutations in the GLTSCR1 gene, leading to truncated proteins that promote metastasis. This GLTSCR1-BRD4 interaction is a potential therapeutic target for CRC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Microsatellite instability (MSI) is common in colorectal cancer (CRC), often causing frameshift mutations.
- The function of many MSI-associated mutations, particularly in tumor suppressor genes, remains unclear.
- Glioma tumor suppressor candidate region gene 1 (GLTSCR1) has been implicated in cancer, but its role in CRC is not fully understood.
Purpose of the Study:
- To investigate the impact of MSI-associated frameshift mutations in GLTSCR1 on colorectal cancer progression.
- To elucidate the molecular mechanism by which GLTSCR1 and its variants regulate gene transcription and CRC metastasis.
- To assess the therapeutic potential of targeting the GLTSCR1-BRD4 interaction in CRC.
Main Methods:
- Identification and characterization of GLTSCR1 frameshift mutations in CRC patient samples.
- Functional assays to assess the role of GLTSCR1 and its truncated variants in cell migration and invasion.
- Co-immunoprecipitation and Western blotting to study protein-protein interactions between GLTSCR1 and BRD4.
- Analysis of RNA Polymerase II phosphorylation status and gene expression profiles.
- Assessment of sensitivity to bromodomain and extra terminal domain (BET) inhibitors in GLTSCR1-deficient cells.
Main Results:
- An MSI-associated frameshift mutation in GLTSCR1 generates two C-terminal-truncated proteins.
- GLTSCR1 functions as a tumor suppressor, inhibiting CRC metastasis by blocking oncogenic transcriptional elongation through interaction with BRD4.
- Truncated GLTSCR1 proteins translocate to the cytoplasm, lose their BRD4 binding domain, and promote oncogenic transcription.
- GLTSCR1 deficiency reduces sensitivity to BET inhibitors, suggesting a role in drug response.
Conclusions:
- MSI-driven GLTSCR1 truncation promotes CRC metastasis by disrupting the GLTSCR1-BRD4 interaction and enhancing oncogenic transcription.
- The GLTSCR1-BRD4 pathway is a critical regulator of CRC metastasis and a potential therapeutic target.
- Targeting the GLTSCR1-BRD4 interaction may offer a novel strategy for CRC treatment, particularly in MSI-positive tumors.
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