2. Academic Validation
  3. ZNF451 favors triple-negative breast cancer progression by enhancing SLUG-mediated CCL5 transcriptional expression

ZNF451 favors triple-negative breast cancer progression by enhancing SLUG-mediated CCL5 transcriptional expression

  • Cell Rep. 2023 Jun 19;42(6):112654. doi: 10.1016/j.celrep.2023.112654.
Yu Zhang 1,  Wanyu Wang 2,  Jiali Min 1,  Suosi Liu 1,  Qianrong Wang 1,  Yu Wang 1,  Yang Xiao 1,  Xia Li 1,  Zhiguang Zhou 1,  Shanshan Liu 3
Affiliations

Affiliations

  • 1 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China.
  • 2 Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3 National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, China. Electronic address: lss0625@csu.edu.cn.
PMID: 37342906 DOI: 10.1016/j.celrep.2023.112654
Abstract

Triple-negative breast Cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC.

Keywords

CCL5; CP: Cancer; ZNF451; peptide; triple-negative breast cancer; tumor microenvironment; tumor-associated macrophages.

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