CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Cell Cycle and Apoptosis Regulator 1 (CCAR1) and CCAR2 are crucial in physiological and pathological processes.
• Their roles in DNA damage response, nuclear receptor function, and Wnt signaling are established.
• Existing literature presents conflicting data on CCAR1 and CCAR2's function as tumor promoters or suppressors.

Purpose of the Study:

• To review mechanistic, preclinical, and human translational findings for CCAR1 and CCAR2.
• To explore the reasons behind their contradictory roles in cancer.
• To highlight CCAR1 and CCAR2 as potential master regulators in metabolism, aging, and cancer.

Main Methods:

• Analysis of RNA and protein expression data from human studies.
• Data mining of The Cancer Genome Atlas (TCGA).
• Review of findings from gene knockout mouse models and cell-based assays.

Main Results:

• CCAR1 and CCAR2 exhibit context-dependent activities influenced by tissue type, genetic background, protein interactions, posttranslational modifications, and alternative splicing.
• Interactions with proteins like β-catenin, androgen receptor, p21, p53, sirtuin 1, and HDAC3 are implicated in their dual roles.
• TP53 mutations significantly impact patient survival outcomes.

Conclusions:

• CCAR1 and CCAR2 function as "gene chameleons" with context-specific roles in cancer.
• Understanding the factors driving their divergent functions is critical for therapeutic strategies.
• Further investigation is needed to fully elucidate CCAR1 and CCAR2's roles in cancer, metabolism, and aging.