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.
Highlights
Frameshift mutations frequently occur in colorectal cancer (CRC) with protein products and result in oncogenic potential when it occurs in coding regions microsatellite instability (MSI), but the nature and biological function of many of genes involved in several crucial func
Polymerase chain reaction (PCR) amplification combined with DNA sequencing was used to further verify heterozygous frameshift mutations with the deletion or insertion of a single cytosine nucleotide in the GLTSCR1 C8 microsatellite site in these CRC samples (Figure 1B); these results were reconfirmed by capillary electrophoresis (Figure 1C)
We demonstrated that GLTSCR1 negatively regulates oncogenic transcriptional elongation and inhibits CRC metastasis through the binding of its BB domain to both the BDs and the Phosphorylation-Dependent Interaction Domain (PDID) of bromodomain protein 4 (BRD4)
Summary
Frameshift mutations frequently occur in colorectal cancer (CRC) with protein products and result in oncogenic potential when it occurs in coding regions microsatellite instability (MSI), but the nature and biological function of many of genes involved in several crucial func-. An MSI frameshift mutation tions and pathways.[3,4] MSI repis identified in glioma tumor suppressor candidate region gene 1 (GLTSCR1) that produces two C-terminal-truncated proteins. Through binding to bromodomains and the phosphorylation-dependent interaction domain resents a molecular hallmark of hereditary nonpolyposis Lynch syndrome and occurs in ≈15–20% of sporadic colorectal cancer (CRC) cases.[5] In addition to CRC, MSI has been observed in endoof bromodomain protein 4 (BRD4) via the C-terminus, GLTSCR1 blocks oncogenic transcriptional elongation. GLTSCR1 is ubiquitously expressed in spleen, prostate, adipose, and colon tissues and
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