2. Academic Validation
  3. Palmitoylation-mediated regulation of KAT2A promotes lung metastasis in breast cancer

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

  • Nat Cell Biol. 2026 Apr;28(4):771-782. doi: 10.1038/s41556-026-01913-z.
Ming Liu 1 2,  Anke Vandekeere 1 2,  Xiao-Zheng Liu 1 2,  Stephan Schenck 3,  Juan Fernández-García 1 2,  Tine Tricot 1 2,  Yiming Peng-Winkler 1 2 4,  Margherita Demicco 1 2,  Dorien Broekaert 1 2,  Ines Vermeire 1 2,  Janine Theile 1 2,  Gitte Zels 5,  Anirudh Pabba 5,  Christine Desmedt 5,  Janine D Brunner 3,  Patricia Altea-Manzano 1 2 6,  Sarah-Maria Fendt 7 8
Affiliations

Affiliations

  • 1 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.
  • 2 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
  • 3 VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium, and Structural Biology Brussels, Vrije Universiteit Brussel, VUB, Brussels, Belgium.
  • 4 Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Dusseldorf, Dusseldorf, Germany.
  • 5 Laboratory for Translational Breast Cancer Research, Department of Oncology, KU Leuven, Belgium.
  • 6 Laboratory of Metabolic Regulation and Signaling in Cancer, Andalusian Molecular Biology and Regenerative Medicine Centre (CABIMER)-University of Seville-CSIC-University Pablo de Olavide, Seville, Spain.
  • 7 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium. [email protected].
  • 8 Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. [email protected].
PMID: 41826695 DOI: 10.1038/s41556-026-01913-z
Abstract

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.

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