{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T11:54:05Z","timestamp":1785498845207,"version":"3.56.0"},"reference-count":42,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"3","funder":[{"DOI":"10.13039\/100031233","name":"Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research","doi-asserted-by":"publisher","award":["2024SQGH002235"],"award-info":[{"award-number":["2024SQGH002235"]}],"id":[{"id":"10.13039\/100031233","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372992, 82073076"],"award-info":[{"award-number":["82372992, 82073076"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82230094"],"award-info":[{"award-number":["82230094"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People's Republic of China","doi-asserted-by":"publisher","award":["2022YFA1104003"],"award-info":[{"award-number":["2022YFA1104003"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,1,16]]},"abstract":"<jats:p>\n                    Crotonate, a short-chain fatty acid, generates protein crotonylation. However, the role of crotonate in cancer progression is unknown. Here, we present a crotonate\u2013crotonyl\u2013coenzyme A (CoA)\u2013enhancer of zeste homolog 2 (EZH2) crotonylation cascade blocking breast cancer growth and metastasis. We demonstrated that crotonate promotes EZH2 degradation via crotonyl-CoA\u2013mediated crotonylation at Lys\n                    <jats:sup>348<\/jats:sup>\n                    in EZH2 (EZH2-K348cr). EZH2-K348cr leads to reduced genome-wide H3K27me3 (trimethylation of lysine-27 on histone-3) occupancy. Crotonate metabolizes to crotonyl-CoA by ACSS2 (acyl-CoA synthetase 2), and then, acyltransferase p300 catalyzes crotonyl-CoA and generates EZH2-K348cr. Crotonylated EZH2 triggers EZH2 ubiquitination and degradation. Administration of crotonate markedly inhibits breast cancer cell growth and metastasis via a crotonate-crotonyl-CoA-EZH2-K348cr cascade. In comparison, crotonate showed better blocking effect than EZH2 inhibitor tazemetostat in suppressing breast cancer metastasis. The combination of crotonate and anti-PD-L1 (programmed cell death ligand 1) antibody enhances responses of breast cancer cells to immunotherapy. Together, our findings indicate that crotonate is a promising anticancer drug candidate that suppresses breast cancer growth and metastasis by specifically inducing EZH2 degradation.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aea9892","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T18:59:06Z","timestamp":1768589946000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":6,"title":["Crotonate suppresses breast cancer metastasis and promotes immunotherapy response by inducing ACSS2-mediated EZH2-K348 crotonylation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6071-5480","authenticated-orcid":true,"given":"Bo","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Duan","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youzhi","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunhao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6751-5349","authenticated-orcid":true,"given":"Yu","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8193-0899","authenticated-orcid":true,"given":"Hongquan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, PKU International Cancer Institute, Peking University Health Science Center, Beijing 100191, China."},{"name":"Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-24331-1"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(78)90305-7"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322269111"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-024-01191-9"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.08.033"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-020-09518-4"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.62347\/ETUQ6763"},{"key":"e_1_3_2_9_2","first-page":"3422","article-title":"Short chain fatty acids exhibit selective estrogen receptor downregulator (SERD) activity in breast cancer","volume":"12","author":"Schoeller A.","year":"2022","unstructured":"A. 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