Identification of a small-molecule compound that inhibits homodimerization of oncogenic NAC1 protein and sensitizes cancer cells to anticancer agents

Xiao Hui Wang, Cheng Ji, Hong Han Zhang, Yu Shan, Yi Jie Ren, Yan Wei Hu, Liang Rong Shi, Ling Chuan Guo, Wei Dong Zhu, Yu Juan Xia, Bei Jia Liu, Zi Yun Rong, Bi Lian Wu, Zhi Jun Ming, Xing Cong Ren, Jian Xun Song, Jin Ming Yang, Yi Zhang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Nucleus accumbens-associated protein-1 (NAC1) is a transcriptional repressor encoded by the NACC1 gene, which is amplified and overexpressed in various human cancers and plays critical roles in tumor development, progression, and drug resistance. NAC1 has therefore been explored as a potential therapeutic target for managing malignant tumors. However, effective approaches for effective targeting of this nuclear protein remain elusive. In this study, we identified a core unit consisting of Met7 and Leu90 in NAC1's N-terminal domain (amino acids 1-130), which is critical for its homodimerization and stability. Furthermore, using a combination of computational analysis of the NAC1 dimerization interface and high-throughput screening (HTS) for small molecules that inhibit NAC1 homodimerization, we identified a compound (NIC3) that selectively binds to the conserved Leu-90 of NAC1 and prevents its homodimerization, leading to proteasomal NAC1 degradation. Moreover, we demonstrate that NIC3-mediated down-regulation of NAC1 protein sensitizes drug-resistant tumor cells to conventional chemotherapy and enhances the antimetastatic effect of the antiangiogenic agent bevacizumab both in vitro and in vivo. These results suggest that small-molecule inhibitors of NAC1 homodimerization may effectively sensitize cancer cells to some anticancer agents and that NAC1 homodimerization could be further explored as a potential therapeutic target in the development of antineoplastic agents.

Original languageEnglish
Pages (from-to)10006-10017
Number of pages12
JournalJournal of Biological Chemistry
Volume294
Issue number25
DOIs
StatePublished - Jun 21 2019

Bibliographical note

Publisher Copyright:
© 2019 Wang et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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