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We aimed to define downstream drivers of the KDM5D effect. Using chromatin immunoprecipitation sequencing (ChIP\u2010seq) of the LNCaP cell line (androgen\u2010sensitive human prostate adenocarcinoma) with and without silenced\n                    <jats:italic>KDM5D, MYBL2<\/jats:italic>\n                    \u2010binding sites were analyzed. Associations between\n                    <jats:italic>MYBL2<\/jats:italic>\n                    mRNA expression and clinical outcomes were assessed in cohorts of men with localized and metastatic hormone\u2010sensitive prostate cancer.\n                    <jats:italic>In\u2009vitro<\/jats:italic>\n                    assays with silencing and overexpression of\n                    <jats:italic>MYBL2<\/jats:italic>\n                    and\n                    <jats:italic>KDM5D<\/jats:italic>\n                    in androgen receptor (AR)\u2010positive hormone\u2010sensitive prostate cancer cell lines, LNCaP and LAPC4, were used to assess their influence on cellular proliferation, apoptosis, and cell cycle distribution, as well as sensitivity to androgen deprivation, docetaxel, and cabazitaxel. We found that silencing\n                    <jats:italic>KDM5D<\/jats:italic>\n                    increased histone H3 lysine K4 (H3K4) trimethylation and increased\n                    <jats:italic>MYBL2<\/jats:italic>\n                    expression.\n                    <jats:italic>KDM5D<\/jats:italic>\n                    and\n                    <jats:italic>MYBL2<\/jats:italic>\n                    were negatively correlated with some but not all clinical samples. Higher\n                    <jats:italic>MYBL2<\/jats:italic>\n                    expression was associated with a higher rate of relapse in localized disease and poorer overall survival in men with metastatic disease in the CHAARTED trial. Lower\n                    <jats:italic>MYBL2<\/jats:italic>\n                    levels enhanced LNCaP and LAPC4 sensitivity to androgen deprivation and taxanes.\n                    <jats:italic>In\u2009vitro<\/jats:italic>\n                    , modifications of\n                    <jats:italic>KDM5D<\/jats:italic>\n                    and\n                    <jats:italic>MYBL2<\/jats:italic>\n                    altered cell cycle distribution and apoptosis in a cell line\u2010specific manner. These results show that the transcription factor\n                    <jats:italic>MYBL2<\/jats:italic>\n                    impacts\n                    <jats:italic>in\u2009vitro<\/jats:italic>\n                    hormone\u2010sensitive prostate cancer sensitivity to androgen deprivation and taxanes, and lower levels are associated with better clinical outcomes in men with hormone\u2010sensitive prostate cancer.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.13314","type":"journal-article","created":{"date-parts":[[2022,9,10]],"date-time":"2022-09-10T09:53:00Z","timestamp":1662803580000},"page":"3994-4010","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Increased\n                    <scp>\n                      <i>MYBL2<\/i>\n                    <\/scp>\n                    expression in aggressive hormone\u2010sensitive prostate cancer"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8834-5051","authenticated-orcid":false,"given":"Yuki","family":"Yoshikawa","sequence":"first","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York NY USA"},{"name":"Department of Urology Osaka Medical and Pharmaceutical University  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konrad H.","family":"Stopsack","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin Victoria","family":"Wang","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"ECOG\u2010ACRIN Biostatistics Center Dana\u2010Farber Cancer Institute  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0265-6970","authenticated-orcid":false,"given":"Ying Z.","family":"Mazzu","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7631-6915","authenticated-orcid":false,"given":"Foster","family":"Burton","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Dana\u2010Farber Cancer Institute  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goutam","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Urology Icahn School of Medicine at Mount Sinai  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Harisha","family":"Rajanala","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9304-9916","authenticated-orcid":false,"given":"Rahim","family":"Hirani","sequence":"additional","affiliation":[{"name":"Department of Medicine Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhiksha","family":"Nandakumar","sequence":"additional","affiliation":[{"name":"Center for Molecular Oncology Memorial Sloan Kettering Cancer Center  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwo\u2010Shu Mary","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Dana\u2010Farber Cancer Institute  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Dana\u2010Farber Cancer Institute  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elai","family":"Davicioni","sequence":"additional","affiliation":[{"name":"Decipher Biosciences Inc.  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