Coiled-coil domain containing 3 suppresses breast cancer growth by protecting p53 from proteasome-mediated degradation

Caiyue Li, Hyemin Lee, Ji Hoon Jung, Yiwei Zhang, Jieqiong Wang, Chang Liu, Roger L. Sheffmaker, Allyson M. Segall, Shelya X. Zeng, Hua Lu

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Coiled-coil domain containing 3 (CCDC3) was previously shown to regulate liver lipid metabolism as a secretory protein. Here, we report an unexpected intracellular role of CCDC3 as a tumor suppressor in breast cancer (BrC). Bioinformatics datasets analysis showed that CCDC3 is under-expressed in BrCs, while its higher levels are correlated with higher overall survival and lower relapse of cancer patients, and CCDC3 is positively correlated with p53 and its target genes. Ectopic CCDC3 markedly suppressed proliferation, colony formation, and xenograft tumor growth by augmenting p53 activity in BrC cells. Depletion of endogenous CCDC3 by CRISPR-Cas9 increased proliferation and drug resistance of BrC cells by alleviating 5-Fluorouracil (5-FU)-induced p53 level and activity. Mechanistically, CCDC3 bound to the C-termini of p53 and MDM2, consequently stabilizing p53 in the nucleus and impairing MDM2 recruitment of p53 to the 26S proteosome without inhibiting p53 ubiquitination. p53 induced CCDC3 expression by binding to its promoter in BrC cells. Our results unveil a unique mechanism underlying CCDC3 activation of p53 in a positive feedback fashion to suppress BrC growth.

Original languageEnglish
Pages (from-to)154-164
Number of pages11
JournalOncogene
Volume42
Issue number2
DOIs
Publication statusPublished - 5 Jan 2023

Bibliographical note

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© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

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