前列腺癌
维甲酸
雄激素受体
下调和上调
生物
癌症研究
基础(医学)
转录组
内科学
内分泌学
癌症
医学
细胞培养
基因
基因表达
遗传学
胰岛素
作者
Samuel P. Pitzen,Amber N. Rudenick,Yinjie Qiu,Weijie Zhang,Sarah A. Munro,Braedan M. McCluskey,Colleen L. Forster,Hannah E. Bergom,Atef Ali,Ella Boytim,John T. Lafin,Simon Linder,Mazlina Ismail,Wout Devlies,Conner J. Sessions,Frank Claessens,Steven Joniau,Gerhardt Attard,Wilbert Zwart,Peter S. Nelson
标识
DOI:10.1073/pnas.2415308122
摘要
Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of RARG uncovered a DNPC sensitivity to growth inhibition by retinoic acid receptor agonists, which down-regulated KLF5 and up-regulated AR. These findings offer CRPC classifications based on prostate epithelial cell identities and nominate KLF5 and RARG as therapeutic targets for CRPC displaying a mixed basal, club, and hillock identity.
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