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

• Published in: Cancer science 2020-10, Vol.111 (10), p.3416-3425
• Main Authors: Johnson, Gavin S., Rajendran, Praveen, Dashwood, Roderick H.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Aging; Alternative splicing; Androgen receptors; Androgens; Animal models; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Ataxia; Biopsy; Bone cancer; Breast cancer; Cancer; CCAR1; CCAR2; Cell culture; Cell cycle; Cell Cycle Proteins - genetics; Colorectal cancer; Cyclin-dependent kinase inhibitor p21; DBC1; Deoxyribonucleic acid; Disease Models, Animal; DNA; DNA damage; Esophageal cancer; Gastric cancer; Gene expression; Genes, Tumor Suppressor; Genomes; GTP-binding protein; Histone deacetylase; Humans; Kinases; Liver cancer; Lymphatic system; Medical prognosis; Metastasis; Mice; Mice, Knockout; Mutation; Nematodes; Neoplasms - genetics; Ovarian cancer; p53 Protein; Promoter Regions, Genetic; Protein arrays; Protein interaction; Proteins; Review; Ribonucleic acid; RNA; Roles; Translation; Tumors; Wnt protein
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.14579

Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) have emerged as key players in physiology and pathophysiology, with critical roles in the DNA damage response, nuclear receptor function, and Wnt signaling, among other activities. Contradictory reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors, suggesting that CCAR1 and CCAR2 have the hallmarks of gene chameleons. We review herein the mechanistic, preclinical, and human translational findings for CCAR1 and CCAR2, based on available RNA and protein expression data from human studies, The Cancer Genome Atlas (TCGA) data mining, gene knockout mouse models, and cell‐based assays. Multiple factors contribute to the divergent activities of CCAR1 and CCAR2, including tissue type, mutation/genetic background, protein‐protein interactions, dynamic regulation via posttranslational modifications, and alternative RNA splicing. An array of protein partners interact with CCAR1 and CCAR2 in the context of tumor promotion and suppression, including β‐catenin, androgen receptor, p21Cip1/Waf1, tumor protein p53 (p53), sirtuin 1, and histone deacetylase 3. Genetic changes frequently found in cancer, such as TP53 mutation, also serve as critical determinants of survival outcomes in cancer patients. This review seeks to provide the impetus for further investigation into CCAR1 and CCAR2 as potential master regulators of metabolism, aging, and cancer. Cell cycle and apoptosis regulator 1 (CCAR1) and CCAR2 have emerged as key players in physiology and pathophysiology, with important roles in Wnt signaling, nuclear receptor function, adipogenesis, and the DNA damage response. Due to the diverse array of protein partners, including beta‐catenin, androgen receptor, p21, p53, sirtuin 1, and histone deacetylase 3, literature reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors. Genetic changes frequently found in cancer, such as TP53 mutation, also serve as critical determinants of patient survival outcomes and impact the roles of CCAR1 and CCAR2 as master regulators of metabolism, aging, and cancer.