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Publications

Journal Article Ahead of print

PubMed: 41992085 DOI: 10.1139/bcb-2025-0446

Acyl-protein thioesterase 1 (LYPLA1) activity promotes the growth of MDA-MB-468 triple-negative breast cancer cells.

Biochem Cell Biol

Authors: Michael Salsaa, Mahtab Tavasoli, Haggag S Zein, Shubhashree Pani, Rahul Kathayat, Bryan Dickinson, Gregory D Fairn

Affiliations

  • Dalhousie University, Department of Pathology, Halifax, Canada. Dalhousie University, Department of Biochemistry & Molecular Biology, Halifax, Canada;.
  • Dalhousie University, Department of Pharmacology, Halifax, Canada;.
  • Dalhousie University, Department of Pathology, Halifax, Canada;.
  • The University of Chicago, Department of Chemistry, Chicago, Illinois, United States;.
  • The University of Chicago, Department of Chemistry, Chicago, Illinois, United States;.
  • The University of Chicago, Department of Chemistry, Chicago, Illinois, United States.
  • Chan Zuckerberg Biohub, San Francisco, United States;.
  • Dalhousie University, Department of Pathology, Halifax, Canada.
  • Dalhousie University, Department of Biochemistry & Molecular Biology, Halifax, Canada;.

Abstract

Protein S-acylation is a lipid-based, often reversible post-translational modification that can regulate many aspects of protein behavior, including subcellular localization, proteininteractions, and activity. Emerging evidence has identified roles for individual protein acyltransferases encoded by the ZDHHC in cancers, yet the roles of de-S-acylation enzymes are less clear. Recent evidence suggests that acyl-protein thioesterase (APT1)/LYPLA1 can impact epithelial-mesenchymal transition and metastasis. This study integrates patient datasets, CRISPR dependency data, and in vitro assays to find APT1 as a context-dependent vulnerability in triple-negative breast cancer (TNBC). Despite the highest protein abundance in luminal A MCF7 cells, basal-like MDA-MB-468 cells exhibited the most prominent specific APT1 activity, reflecting subtype-specific regulation. Inhibition of APT1 with ML348 increased S-acylation of nuclear and mitochondrial proteins without altering global acylation. Functionally, APT1 inhibition reduced cell proliferation while inducing minimal apoptosis, consistent with cytostatic growth arrest. Cell-cycle analysis revealed G1 accumulation and reduced S/G2 transition, linking proteomic changes to impaired replication. These findings establish APT1 as a regulator of TNBC proliferation through dynamic de-S-acylation of cell-cycle and mitochondrial proteins, highlighting it as a potential therapeutic vulnerability in aggressive breast cancers.

MeSH

Cells, Triple Negative Breast Neoplasms, Mitochondrial Proteins, Growth, Biochemistry, Breast Neoplasms, Neoplasms, Cell Biology, Breast