DCAF13 promotes breast cancer cell proliferation by ubiquitin inhibiting PERP expression
Shan, Bao Qian; Wang, Xiao Min; Zheng, Li; Han, Yao; Gao, Jie; Lv, Meng Dan; Zhang, Yi; Liu, Yi Xuan; Zhang, Han; Chen, Hao Sa; Ao, Lei; Zhang, Yin Li; Lu, Xiang; Wu, Zhong Jie; Xu, Ying; Che, Xuan; Heger, Michal; Cheng, Shu Qun; Pan, Wei Wei; Zhang, Xin
(2022) Cancer Science, volume 113, issue 5, pp. 1587 - 1600
(Article)
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
... read more
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.
show less
Download/Full Text
Keywords: breast cancer, CRL4, DCAF13, DDB1, PERP, post-translational modification, ubiquitin E3 ligase, Oncology, Cancer Research
ISSN: 1347-9032
Publisher: Wiley-Blackwell
Note: Funding Information: The National Natural Science Foundation of China (Grant Number: 31871402, 31701260), the Natural Science Foundation of Zhejiang Province (Grant Number: LY21H160047, LY17H160060, LGD21H160003, LZ20H16004), the Jiaxing Science and Technology Bureau project (Grant Number: 2020AD10018, 2020AD30073, 00320117AL), the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics (Grant Number: 12.2019), the Zhejiang Provincial Foreign Expert Grant (Grant Number: 12.2018), the Dutch Cancer Foundation (Grant Number: KWF, 10666), the Jiaxing University Scientific Research Start‐up project (Grant Number: CD70519018), the National College Student Innovation and Entrepreneurship Training Program (Grant Number: 202010354043, 202010354042, 2020R417015, 202110354015, 2021R417023, 2021R417028, 202113291002, 202113291003) Funding Information: The National Natural Science Foundation of China (Grant Number: 31871402, 31701260), the Natural Science Foundation of Zhejiang Province (Grant Number: LY21H160047, LY17H160060, LGD21H160003, LZ20H16004), the Jiaxing Science and Technology Bureau project (Grant Number: 2020AD10018, 2020AD30073, 00320117AL), the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics (Grant Number: 12.2019), the Zhejiang Provincial Foreign Expert Grant (Grant Number: 12.2018), the Dutch Cancer Foundation (Grant Number: KWF, 10666), the Jiaxing University Scientific Research Start-up project (Grant Number: CD70519018), the National College Student Innovation and Entrepreneurship Training Program (Grant Number: 202010354043, 202010354042, 2020R417015, 202110354015, 2021R417023, 2021R417028, 202113291002, 202113291003) This work was supported by the National Natural Science Foundation of China (31871402, 31701260), the Natural Science Foundation of Zhejiang Province (LY21H160047, LY17H160060, LGD21H160003, LZ20H16004), the Jiaxing Science and Technology Bureau project (2020AD10018, 2020AD30073, 00320117AL), the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics (12.2019), the Zhejiang Provincial Foreign Expert Grant (12.2018), the Dutch Cancer Foundation (KWF, 10666), the Jiaxing University Scientific Research Start-up project (CD70519018), the National College Student Innovation and Entrepreneurship Training Program (202010354043, 202010354042, 2020R417015, 202110354015, 2021R417023, 2021R417028, 202113291002, 202113291003), the Jiaxing talent pioneer innovation team, and the key Laboratory of Medical Electronics and Digital Health of Zhejiang Province. Funding Information: This work was supported by the National Natural Science Foundation of China (31871402, 31701260), the Natural Science Foundation of Zhejiang Province (LY21H160047, LY17H160060, LGD21H160003, LZ20H16004), the Jiaxing Science and Technology Bureau project (2020AD10018, 2020AD30073, 00320117AL), the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics (12.2019), the Zhejiang Provincial Foreign Expert Grant (12.2018), the Dutch Cancer Foundation (KWF, 10666), the Jiaxing University Scientific Research Start‐up project (CD70519018), the National College Student Innovation and Entrepreneurship Training Program (202010354043, 202010354042, 2020R417015, 202110354015, 2021R417023, 2021R417028, 202113291002, 202113291003), the Jiaxing talent pioneer innovation team, and the key Laboratory of Medical Electronics and Digital Health of Zhejiang Province. Publisher Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
(Peer reviewed)
