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<p>Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that <i>KAT2A</i> expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name <i>ZDHHC20</i>) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of <i>KAT2A</i>. Accordingly, <i>Zdhhc20</i> and <i>Tm4sf1</i> silencing as well as expression of a <i>Tm4sf1</i> double palmitoylation mutant decreases lung metastasis growth, which is rescued by <i>Kat2a</i> expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.</p>

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Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer

  • 期刊论文

  • 发表日期：

    2026年3月13日

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  • Ming Liu,
  • Anke Vandekeere,
  • Xiao-Zheng Liu,
  • Stephan Schenck,
  • Juan Fernández-García,
  • Tine Tricot,
  • Yiming Peng-Winkler,
  • Margherita Demicco,
  • Dorien Broekaert,
  • Ines Vermeire,
  • Janine Theile,
  • Gitte Zels,
  • Anirudh Pabba,
  • Christine Desmedt,
  • Janine D. Brunner,
  • Patricia Altea-Manzano,
  • Sarah-Maria Fendt

摘要

Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that KAT2A expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name ZDHHC20) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of KAT2A. Accordingly, Zdhhc20 and Tm4sf1 silencing as well as expression of a Tm4sf1 double palmitoylation mutant decreases lung metastasis growth, which is rescued by Kat2a expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.