Deletion of a pseudogene within a fragile site triggers the oncogenic expression of the mitotic CCSER1 gene

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• Common fragile sites (CFS) are genomic regions prone to breakage during replication stress, with their role in oncogenesis being debated.
• While most genes within CFS deletions are downregulated, some are paradoxically overexpressed, suggesting complex regulatory mechanisms.

Purpose of the Study:

• To investigate the controversial oncogenic role of common fragile sites (CFS) in cancer.
• To elucidate the mechanism by which certain CFS deletions lead to gene overexpression and contribute to tumorigenesis.

Main Methods:

• Analysis of The Cancer Genome Atlas (TCGA) dataset to identify gene expression patterns within CFS deletions.
• Investigated the FRA4F fragile site and its association with the CCSER1 gene and TMSB4XP8 pseudogene.
• Functional studies to assess the impact of TMSB4XP8 ablation or silencing on CCSER1 expression and cellular phenotypes.

Main Results:

• Identified FRA4F, a frequent CFS, where deletion leads to CCSER1 overexpression via cis-acting regulation involving the TMSB4XP8 pseudogene.
• CCSER1 overexpression promotes increased proliferation, centrosome amplification, multinuclearity, and aberrant mitoses.
• FRA4F deletions correlate with mitotic gene deregulation and genomic instability in patient samples.
• Cells overexpressing CCSER1 exhibit sensitivity to aurora kinase inhibitors.

Conclusions:

• Discovered a novel oncogenic mechanism where focal deletions at CFS activate "dormant" oncogenes like CCSER1.
• CCSER1 acts as a tumor promoter by inducing genomic instability and proliferation.
• Findings suggest aurora kinase inhibitors as a potential therapeutic strategy for cancers with CCSER1 overexpression due to FRA4F deletions.