Mechanistic insights of NAC1 nuclear export and its role in ovarian cancer resistance to docetaxel

Shun Li Dong, Xiao Hui Wang, Shu Min Yang, Fan Fan Guo, Jing Jing Zhang, Cheng Ji, Liang Rong Shi, Yan Cheng, Yan Wei Hu, Zhen Yun Li, Lei Peng, Ling Chuan Guo, Wei Dong Zhu, Xingcong Ren, Jin Ming Yang, Yi Zhang

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

In this study, we uncovered the nuclear export of nucleus accumbens-associated protein-1 (NAC1) as a novel mechanism involved in ovarian cancer resistance to taxanes, the chemotherapeutic drugs commonly used in treatment of this malignancy. We showed that NAC1, a nuclear factor of the BTB/POZ gene family, has a nuclear export signal (NES) at the N terminus (aa 17–28), and this NES critically contributes to the NAC1 nuclear-cytoplasmic shuttling when tumor cells were treated with docetaxel. Mechanistically, the nuclear-exported NAC1 bound to cullin3 (Cul3) and Cyclin B1 via its BTB and BOZ domains respectively, and the cyto-NAC1-Cul3 E3 ubiquitin ligase complex promotes the ubiquitination and degradation of Cyclin B1, thereby facilitating mitotic exit and leading to cellular resistance to docetaxel. We also showed in in vitro and in vivo experiments that TP-CH-1178, a membrane-permeable polypeptide against the NAC1 NES motif, blocked the nuclear export of NAC1, interfered with the degradation of Cyclin B1 and sensitized ovarian cancer cells to docetaxel. This study not only reveals a novel mechanism by which the NAC1 nuclear export is regulated and Cyclin B1 degradation and mitotic exit are impacted by the NAC1-Cul3 complex, but also provides the nuclear-export pathway of NAC1 as a potential target for modulating taxanes resistance in ovarian cancer and other malignancies.

Original languageEnglish
Article number115533
JournalBiochemical Pharmacology
Volume211
DOIs
StatePublished - May 2023

Bibliographical note

Publisher Copyright:
© 2023 Elsevier Inc.

Keywords

  • CUL3
  • Cyclin B1
  • Docetaxel
  • Nuclear-exported NAC1
  • Sensitivity

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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