The stress phenotype makes cancer cells addicted to CDT2, a substrate receptor of the CRL4 ubiquitin ligase

Abstract

CDT2/L2DTL/RAMP is one of the substrate receptors of the Cullin Ring Ubiquitin Ligase 4 that targets for ubiquitin mediated degradation a number of substrates, such as CDT1, p21 and CHK1, involved in the regulation of cell cycle and survival. Here we show that CDT2 depletion was alone able to induce the apoptotic death in 12/12 human cancer cell lines from different tissues, regardless of the mutation profile and CDT2 expression level. Cell death was associated to rereplication and to loss of CDT1 degradation. Conversely, CDT2 depletion did not affect non-transformed human cells, such as immortalized kidney, lung and breast cell lines, and primary cultures of endothelial cells and osteoblasts. The ectopic over-expression of an activated oncogene, such as the mutation-activated RAS or the amplified MET in non-transformed immortalized breast cell lines and primary human osteoblasts, respectively, made cells transformed in vitro, tumorigenic in vivo, and susceptible to CDT2 loss. The widespread effect of CDT2 depletion in different cancer cells suggests that CDT2 is not in a synthetic lethal interaction to a single specific pathway. CDT2 likely is a non-oncogene to which transformed cells become addicted because of their enhanced cellular stress, such as replicative stress and DNA damage.

The Identification of Potential Therapeutic Targets for Cutaneous Squamous Cell Carcinoma

“…We observed that CDT2 depletion caused cSCC-selective DNA re-replication and DNA damage and that CDT2 knockdowneinduced death in cSCC cells was SET8-dependent ( Figure 5cee and Supplementary Figure S5a). This is consistent with a key role of rereplication in the antitumor activity of CDT2 suppression (Benamar et al, 2016;Olivero et al, 2014).…”

The Multifunctions of WD40 Proteins in Genome Integrity and Cell Cycle Progression

“…The CRL4 L2DTL E3 ligase can promote the ubiquitination of proteins in S phase and after DNA damage 49 . Numerous substrates of CRL4 L2DTL E3 ligase have been identified, such as CDT1, the CDK inhibitor, the histone methyltransferase Set8, the histone acetyltransferases GCN5, the checkpoint kinase CHK1 and the TOB anti-proliferative protein 54 . EED can strongly interact with CUL4A-DDB1 and participate in regulating the methylation of H3 histone at K9 and K27 49 .…”

The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications

“…Overexpression of CDT2, one substrate receptor of CRL4, has been reported in many types of tumors such as breast [ 128 ], gastric [ 129 ], and ovarian carcinomas [ 121 ]. Silencing of CDT2 results in apoptotic death in cancer cells but not in non-transformed cells [ 130 ]. This suggests loss of CDT2 affects viability of cancer cells.…”