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

Abstract

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, p21^Cip1/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.

Keywords: CCAR1; CCAR2; DBC1; apoptosis; cell cycle.

Figure 1

Comparison of protein domains in Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) with the common ancestor Lateral Signaling Target‐3 (LST‐3) in Caenorhabditis elegans. CC, protein‐protein interaction domain; LZ, leucine zipper; NLS, nuclear localization signal; S1‐like, homology to an RNA interaction domain; SAP, homology to DNA‐binding motif for chromosomal organization

Figure 2

A, Cell Cycle and Apoptosis Regulator 1 (CCAR1) and B, Cell Cycle and Apoptosis Regulator 2 (CCAR2) protein partners leading to tumor suppression (cyan), promotion (pink), or potential antagonistic duality (grey). Green arrows = activation; red lines = inhibition; grey lines = not fully elucidated; dashed lines = predicted interactions. For all other abbreviations, refer to the Abbreviations section

Figure 3

A‐C, Overall survival (OS) in liver, renal, and ovarian cancer patients with high vs low CCAR1 mRNA expression in tumors. D‐F, immunodetection of nuclear Cell Cycle and Apoptosis Regulator 1 (CCAR1) for the corresponding tumor types shown in A‐C; immunohistochemistry (IHC) images were obtained from the Human Protein Atlas (https://www.proteinatlas.org/)

Figure 4

A‐C, OS in liver, cervical, and renal cancer patients with high vs low CCAR2 mRNA expression. D‐F, immunodetection of nuclear Cell Cycle and Apoptosis Regulator 2 (CCAR2) for the tumor types shown in A‐C; IHC images were obtained from the Human Protein Atlas, see Figure 3 legend

Figure 5

High CCAR2 expression (red lines) predicted favorable survival outcomes in A, breast, B, colon, and C, prostate cancer, but poor survival in D, large B‐cell lymphoma, E, kidney clear cell carcinoma, and F, renal chromophobe carcinoma. Results from The Cancer Genome Atlas (TCGA) database indicating overall patient survival (OS), except for recurrence‐free survival (RFS) in panel C

Figure 6

Kaplan‐Meier curves for CCAR2 and TP53 mutation status in glioma. Results from The Cancer Genome Atlas (TCGA) database indicating recurrence‐free survival (RFS), all panels. A, Comparison of CCAR2 high vs CCAR2 low expression; B, comparison of TP53 wild type vs TP53 mutant status; C, wild type TP53 with CCAR2 high vs CCAR2 low expression as a covariate; D, mutant TP53 with CCAR2 high vs CCAR2 low as a covariate. Mut, mutant TP53; WT, wild‐type TP53