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

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Cell Reports. 2023 Jun;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

• 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.