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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\u2013mesenchymal 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.<\/jats:p>","DOI":"10.1139\/bcb-2025-0446","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:00:57Z","timestamp":1776398457000},"page":"1-12","update-policy":"https:\/\/doi.org\/10.1139\/csp-crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Acyl-protein thioesterase 1 (\n                    <i>LYPLA1<\/i>\n                    ) activity promotes the growth of MDA-MB-468 triple-negative breast cancer cells"],"prefix":"10.1139","volume":"104","author":[{"given":"Michael","family":"Salsaa","sequence":"first","affiliation":[{"name":"Dalhousie University","place":["Halifax, Canada"]},{"name":"Dalhousie University","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahtab","family":"Tavasoli","sequence":"additional","affiliation":[{"name":"Dalhousie University","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haggag S.","family":"Zein","sequence":"additional","affiliation":[{"name":"Dalhousie University","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubhashree","family":"Pani","sequence":"additional","affiliation":[{"name":"University of Chicago","place":["Chicago, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahul S.","family":"Kathayat","sequence":"additional","affiliation":[{"name":"University of Chicago","place":["Chicago, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bryan C.","family":"Dickinson","sequence":"additional","affiliation":[{"name":"University of Chicago","place":["Chicago, USA"]},{"name":"Chan Zuckerberg Biohub","place":["Chicago, USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory D.","family":"Fairn","sequence":"additional","affiliation":[{"name":"Dalhousie University","place":["Halifax, Canada"]},{"name":"Dalhousie University","place":["Halifax, Canada"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"155","reference":[{"issue":"11","key":"refg1\/ref1","first-page":"1233","volume":"22","author":"Anders C.","year":"2008","journal-title":"Oncology (Williston Park, N.Y.)"},{"key":"refg2\/ref2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00763-x"},{"key":"refg3\/ref3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2012.06.020"},{"key":"refg4\/ref4","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-023-02596-8"},{"key":"refg5\/ref5","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17862-6"},{"key":"refg6\/ref6","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-586511"},{"key":"refg7\/ref7","doi-asserted-by":"publisher","DOI":"10.1186\/s13578-020-00493-1"},{"key":"refg8\/ref8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000265"},{"key":"refg9\/ref9","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834"},{"key":"refg10\/ref10","doi-asserted-by":"publisher","DOI":"10.3390\/life15010126"},{"key":"refg11\/ref11","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-019-0399-y"},{"key":"refg12\/ref12","doi-asserted-by":"publisher","DOI":"10.1039\/C3MD00333G"},{"key":"refg13\/ref13","doi-asserted-by":"publisher","unstructured":"DepMap. 2024. 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