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

Ming Liu1,2, Anke Vandekeere1,2, Xiao-Zheng Liu1,2

  • 1Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium.

Nature Cell Biology
|March 14, 2026
PubMed

Insights

Lysine acetyltransferase 2A (KAT2A) expression in breast cancer lung metastases is regulated by palmitoylation. This pathway involves DHHC20, TM4SF1, and STAT3, impacting metastasis growth.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Acetylation is frequently altered in cancer, with inhibitors targeting acetyltransferases and deacetylases in development.
  • Understanding the regulation of acetyltransferase and deacetylase expression is crucial for cancer therapy.
  • Lysine acetyltransferase 2A (KAT2A) is a key player in multiple cancers, and a KAT2A inhibitor is in clinical trials.

Purpose of the Study:

  • To investigate the regulatory mechanisms controlling KAT2A expression in cancer.
  • To elucidate the role of palmitoylation in KAT2A regulation within breast cancer metastases.

Main Methods:

  • Investigated the role of DHHC20 and TM4SF1 in KAT2A regulation using cell models.
  • Utilized gene silencing and mutant expression to assess the impact on metastasis.
  • Analyzed patient-derived lung metastasis samples to confirm findings in a clinical context.

Main Results:

  • DHHC20 palmitoylates TM4SF1, enhancing its plasma membrane localization.
  • TM4SF1 promotes STAT3 phosphorylation, which acts as a transcriptional regulator of KAT2A.
  • Silencing DHHC20 or TM4SF1, or using a TM4SF1 mutant, reduced lung metastasis growth, an effect rescued by KAT2A expression.
  • Evidence of this regulatory pathway was found in human breast cancer lung metastasis samples.

Conclusions:

  • Palmitoylation, via the DHHC20-TM4SF1-STAT3 axis, regulates KAT2A expression in breast cancer lung metastases.
  • This pathway represents a novel therapeutic target for managing metastatic breast cancer.

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