Ccdc6 knock-in mice develop thyroid hyperplasia associated to an enhanced CREB1 activity

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• CCDC6 (coiled-coil domain containing 6) interacts with CREB1 (cAMP response element-binding protein 1) and represses its transcriptional activity.
• Rearrangements involving CCDC6 and RET create the RET/PTC1 oncogene, leading to loss of CCDC6 function in thyroid papillary carcinomas.
• The coiled-coil domain of CCDC6, encoded by exon 2, is crucial for its function.

Purpose of the Study:

• To investigate the role of CCDC6 functional impairment in thyroid papillary carcinoma development.
• To generate and characterize mice with a mutated Ccdc6 gene, specifically lacking exon 2.
• To assess the impact of CCDC6 exon 2 deletion on CREB1 transcriptional activity and downstream gene expression.

Main Methods:

• Engineered a murine Ccdc6 construct with exon 2 deletion, showing reduced repression of CREB1 activity compared to wild-type.
• Generated Ccdc6-ex2 knock-in mice to model CCDC6 functional loss.
• Analyzed thyroid tissue for hyperplasia, CREB1 activity, and expression of CREB-1 regulated genes.

Main Results:

• Ccdc6-ex2 knock-in mice exhibited thyroid hyperplasia.
• These mice showed enhanced CREB1 activity.
• Increased expression of CREB-1 regulated genes was observed in the knock-in mice.

Conclusions:

• Functional impairment of CCDC6, specifically the loss of exon 2, contributes to thyroid papillary carcinoma development.
• Enhanced CREB1 activity and its downstream targets are implicated in CCDC6-associated thyroid tumorigenesis.
• These findings highlight CCDC6's role as a tumor suppressor in thyroid cancer.