Functional characterization of full-length BARD1 strengthens its role as a tumor suppressor in neuroblastoma

Abstract

BARD1 is associated with the development of high-risk neuroblastoma patients. Particularly, the expression of full length (FL) isoform, FL BARD1, correlates to high-risk neuroblastoma development and its inhibition is sufficient to induce neuroblastoma cells towards a worst phenotype. Here we have investigated the mechanisms of FL BARD1 in neuroblastoma cell lines depleted for FL BARD1 expression. We have shown that FL BARD1 expression protects the cells from spontaneous DNA damage and from damage accumulated after irradiation. We demonstrated a role for FL BARD1 as tumor suppressor to prevent unscheduled mitotic entry of DNA damaged cells and to lead to death cells that have bypassed cell cycle checkpoints. FL BARD1-depleted cells that have survived to checkpoints acquire features of aggressiveness. Overall, our results show that FL BARD1 may defend cells against cancer and prevent malignant transformation of cells.

The Effects of Genetic and Epigenetic Alterations of BARD1 on the Development of Non-Breast and Non-Gynecological Cancers

“…In this review, the role of BARD1-FL as well as different SNPs in BARD1 gene and alternatively spliced forms of BARD1 in non-breast and non-gynecological cancers were discussed and also summarized in Figure 2 , Table 1 , and Supplemental Tables S1 and S2 . BARD1-FL has been widely accepted as a tumor suppressor [ 1 , 2 , 13 , 96 ]. In CRC and NSCLC, the expression of BARD1-FL was associated with increased survival [ 14 , 18 , 101 ], while the SNP rs7585356, which overexpressed BARD1-FL, was associated with decreased susceptibility to high-risk NB [ 86 , 89 ].…”

“…Nonetheless, the expression of BARD1-FL can have acquired oncogenic function in tumors where the upregulation of the DDR genes contributes to resistance to DNA damaging agents [ 108 , 109 ]. BARD1 isoforms caused by genetic mutations or SNPs are upregulated in many tumors [ 13 , 14 , 18 , 96 , 122 ]. Interestingly, few of the genetic mutations discussed here are present in and influence the risk of developing breast and gynecological cancers, suggesting that some of these BARD1 SNPs may be cancer-specific ( Supplementary Tables S1 and S2 ) [ 19 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 ].…”

“…In summary, BARD1-FL acts as a tumor suppressor in the development of NB, primarily by regulating DDR, cellular proliferation, and programmed cell death. BARD1-FL promotes DDR through G2-M checkpoint arrest via downregulation of cyclin B and induction of apoptosis via phosphorylation of p53 [ 96 ]. It is hypothesized that the cell cycle arrest is through the BARD1-BRCA1 heterodimer while cell death was BRCA1-independent, but the mechanisms were not directly tested.…”

The Function of BARD1 in Centrosome Regulation in Cooperation with BRCA1/OLA1/RACK1

“…BARD1 generates several transcripts by alternative splicing, which results in the deletion of the RING domain and/or ANK repeats (Figure 4). BARD1 was recently proposed to play a dual role in cancer [73,74]. Full-length BARD1 (FL-BARD1) functions as a tumor suppressor, whereas aberrant splice variants, BARD1 isoforms, play an oncogenic role.…”

Downregulation of MEG3 promotes neuroblastoma development through FOXO1-mediated autophagy and mTOR-mediated epithelial-mesenchymal transition

“…Tumors are composed of undifferentiated neuroblasts. NB mainly occurs in children with nearly half of NB cases occurring in infants younger than 2 years of age [2,3]. NB has complex clinical manifestations and can occur in different parts of the body [4].…”