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Published on: July 25, 2020
Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers
Daniel Hagerstrand1, Alexander Tong, Steven E Schumacher
11Departments of Medical Oncology and 2Cancer Biology; 3Center for Cancer Genome Discovery, Dana-Farber Cancer Institute;4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and 6Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina.
Unlabelled:
3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain.
Significance:
These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions.
Insights
Researchers identified TLOC1 and SKIL as key cancer driver genes within the 3q26 amplified region. These genes promote tumor growth and invasion, highlighting the importance of co-amplified genes in cancer development.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- The 3q26 chromosomal region is frequently amplified in various cancers, containing approximately 20 genes.
- Identifying specific driver genes within amplified regions is crucial for understanding cancer development and identifying therapeutic targets.
Purpose of the Study:
- To identify cancer driver genes within the amplified 3q26 region.
- To elucidate the functional roles of TLOC1 and SKIL in cancer cell proliferation, growth, and invasion.
Main Methods:
- Utilized loss- and gain-of-function genetic screens to interrogate gene function.
- Performed proteomic studies to identify protein interactions.
- Assessed anchorage-independent growth, cell invasion, and subcutaneous tumor formation.
Main Results:
- TLOC1 (SEC62) was essential for the proliferation of cancer cells with 3q26 amplification and induced anchorage-independent growth.
- SKIL (SNON) promoted cell invasion, and co-expression of TLOC1 and SKIL led to subcutaneous tumor growth.
- TLOC1 interacts with DDX3X, impacting protein translation, while SKIL upregulates SLUG (SNAI2) to enhance invasion.
Conclusions:
- TLOC1 and SKIL are identified as driver genes within the 3q26 amplified region.
- Co-amplified genes in regions of somatic copy number gain can possess complementary functions, driving cancer progression.
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