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Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate
Lizhong Wang1, Runhua Liu, Weiquan Li
1Division of Immunotherapy, Department of Surgery, University of Michigan School of Medicine and Cancer Center, Ann Arbor, MI 48109, USA.
Abstract:
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here, we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly overexpressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Because the male has only one X chromosome, our data represent a paradigm of "single genetic hit" inactivation-mediated carcinogenesis.
Insights
The FOXP3 gene on the X chromosome acts as a prostate tumor suppressor. Inactivating mutations in FOXP3 drive prostate cancer by allowing the oncogene cMYC to overexpress.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Prostate cancer genetics research has primarily focused on autosomal genes.
- Epidemiological and genetic data suggest a role for X-linked factors in prostate cancer risk.
Purpose of the Study:
- To investigate the role of X-linked genes in prostate cancer.
- To identify specific X-linked genes involved in prostate tumorigenesis.
Main Methods:
- Analysis of somatic mutations and deletions in the X-linked FOXP3 gene in human prostate cancer tissues.
- Lineage-specific ablation of FoxP3 in mouse prostate epithelial cells.
- Investigation of FOXP3's transcriptional regulation of cMYC.
Main Results:
- Somatic inactivating mutations and deletion of the X-linked FOXP3 gene were identified in human prostate cancer.
- FoxP3 ablation in mouse prostate epithelial cells induced hyperplasia and intraepithelial neoplasia.
- FOXP3 was found to be necessary and sufficient to repress cMYC expression.
Conclusions:
- FOXP3 functions as an X-linked prostate tumor suppressor in males.
- Inactivation of FOXP3 contributes to prostate carcinogenesis through the dysregulation of cMYC.
- This study presents a paradigm of single genetic hit inactivation in X-linked carcinogenesis.
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