%0 Journal Article
%T ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.
%A Qian C
%A Yang Q
%A Rotinen M
%A Huang R
%A Kim H
%A Gallent B
%A Yan Y
%A Cadaneanu RM
%A Zhang B
%A Kaochar S
%A Freedland SJ
%A Posadas EM
%A Ellis L
%A Di Vizio D
%A Morrissey C
%A Nelson PS
%A Brady L
%A Murali R
%A Campbell MJ
%A Yang W
%A Knudsen BS
%A Mostaghel EA
%A Ye H
%A Garraway IP
%A You S
%A Freeman MR
%J Nucleic Acids Res
%V 52
%N 13
%D 2024 Jul 22
%M 38932701
%F 19.16
%R 10.1093/nar/gkae547
%X Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.