DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression

Abstract

Evolutionarily conserved DDB1‐and CUL4‐associated factor 13 (DCAF13) is a recently discovered substrate receptor for the cullin RING‐finger ubiquitin ligase 4 (CRL4) E3 ubiquitin ligase that regulates cell cycle progression. DCAF13 is overexpressed in many cancers, although its role in breast cancer is currently elusive. In this study we demonstrate that DCAF13 is overexpressed in human breast cancer and that its overexpression closely correlates with poor prognosis, suggesting that DCAF13 may serve as a diagnostic marker and therapeutic target. We knocked down DCAF13 in breast cancer cell lines using CRISPR/Cas9 and found that DCAF13 deletion markedly reduced breast cancer cell proliferation, clone formation, and migration both in vitro and in vivo. In addition, DCAF13 deletion promoted breast cancer cell apoptosis and senescence, and induced cell cycle arrest in the G1/S phase. Genome‐wide RNAseq analysis and western blotting revealed that loss of DCAF13 resulted in both mRNA and protein accumulation of p53 apoptosis effector related to PMP22 (PERP). Knockdown of PERP partially reversed the hampered cell proliferation induced by DCAF13 knockdown. Co‐immunoprecipitation assays revealed that DCAF13 and DNA damage‐binding protein 1 (DDB1) directly interact with PERP. Overexpression of DDB1 significantly increased PERP polyubiquitination, suggesting that CRL4DCAF13 E3 ligase targets PERP for ubiquitination and proteasomal degradation. In conclusion, DCAF13 and the downstream effector PERP occupy key roles in breast cancer proliferation and potentially serve as prognostics and therapeutic targets.

A multidimensional pan‐cancer analysis of DCAF13 and its protumorigenic effect in lung adenocarcinoma

“…Ubiquitin‐mediated protein degradation system is a vital cellular machinery to maintain cell and tissue homeostasis in eukaryotes. DCAF13 is a substrate recognition protein in E3 ubiquitin ligase which involves in the progression of several tumors and embryonic development 12–15,17 . Here, we analyzed the role of DCAF13 in pan‐cancer from a holistic perspective for the first time.…”

“…CRL4B‐DCAF13 mediates polyubiquitination and degradation of phosphatase and tensin homolog (PTEN) to promote osteosarcoma cell growth 13 or support oocyte meiotic resumption 14 . DCAF13 targets ubiquitinated degradation of P53 apoptosis effector related to PMP22 (PERP) to promote breast cancer cell proliferation 15 . The second function is to act as an RNA‐binding protein, regulating the stability of Deltex E3 ubiquitin ligase 3 ( DTX3 ) mRNA to promote triple‐negative breast cancer (TNBC) metastasis 16 .…”

Integrated single-cell and bulk RNA sequencing analysis identifies the predictive signature for prognosis and neoadjuvant chemotherapy responses in breast cancer

“…These pathways have been implicated in several types of cancer and suggest that the differentially expressed genes identi ed in our study may play critical roles in regulating BC pathogenesis [29][30][31]. The nding that broblast, cancer cell, and cycling cell types have relatively high expression of NAC-related genes is particularly relevant as these cells are known to play important roles in BC pathogenesis [32][33][34][35].…”

Hypoxia-Regulated lncRNA USP2-AS1 Drives Head and Neck Squamous Cell Carcinoma Progression

“…DCAF13 has been reported to function as an oncogenic E3 ligase in breast cancer and osteosarcoma by the targeting and degradation of tumor suppressors PERP [ 31 ] and PTEN [ 32 ], respectively. In the current study, we used UbiBrowser 2.0, a useful tool for predicting ubiquitin ligase/deubiquitinase–substrate interactions [ 33 ], to predict the putative substrates of DCAF13.…”