MYC-Mediated Ribosomal Gene Expression Sensitizes Enzalutamide-resistant Prostate Cancer Cells to EP300/CREBBP Inhibitors

被引：19

作者：

Furlan, Tobias ^{[1
]}

Kirchmair, Alexander ^{[2
]}

Sampson, Natalie ^{[1
]}

Puhr, Martin ^{[1
]}

Gruber, Martina ^{[1
]}

Trajanoski, Zlatko ^{[2
]}

Santer, Frederic R. ^{[1
]}

Parson, Walther ^{[3
,4
]}

Handle, Florian ^{[1
]}

Culig, Zoran ^{[1
]}

机构：

[1] Med Univ Innsbruck, Dept Urol, Innsbruck, Austria

[2] Med Univ Innsbruck, Inst Bioinformat, Innsbruck, Austria

[3] Med Univ Innsbruck, Inst Legal Med, Innsbruck, Austria

[4] Penn State Univ, Forens Sci Program, University Pk, PA 16802 USA

来源：

AMERICAN JOURNAL OF PATHOLOGY | 2021年 / 191卷 / 06期

基金：

奥地利科学基金会;

关键词：

ANDROGEN RECEPTOR; GLUCOCORTICOID-RECEPTOR; BINDING PROTEIN; P300; CBP; ANTIANDROGEN; ACETYLATION; PROGRESSION; SURVIVAL;

D O I：

10.1016/j.ajpath.2021.02.017

中图分类号：

R36 [病理学];

学科分类号：

100104 ;

摘要：

Patients with advanced prostate cancer are frequently treated with the antiandrogen enzalutamide. However, resistance eventually develops in virtually all patients, and various mechanisms have been associated with this process. The histone acetyltransferases EP300 and CREBBP are involved in regulation of cellular events in advanced prostate cancer. This study investigated the role of EP300/CREBBP inhibitors in enzalutamide-resistant prostate cancer. EP300/CREBBP inhibitors led to the same inhibition of androgen receptor activity in enzalutamide-resistant and -sensitive cells. However, enzalutamide-resistant cells were more sensitive to these inhibitors in viability assays. As indicated by the RNA-sequencing-based pathway analysis, genes related to the ribosome and MYC activity were significantly altered upon EP300/CREBBP inhibitor treatment. EP300/CREBBP inhibitors led to the down-regulation of ribosomal proteins RPL36 and RPL29. High-level ribosomal proteins amplifications and MYC amplifications were observed in castrationresistant prostate cancer samples of the publicly available Stand Up to Cancer data set. An inhibitor of RNA polymerase I-mediated transcription was used to evaluate the functional implications of these findings. The enzalutamide-resistant cell lines were more sensitive to this treatment. In addition, the migration rate of enzalutamide-resistant cells was strongly inhibited by this treatment. Taken together, the current data show that EP300/CREBBP inhibitors affect the MYC/ribosomal protein axis in enzalutamide-resistant cells and may have promising therapeutic implications. (Am J Pathol 2021, 191: 1094-1107; https://doi.org/

引用

页码：1094 / 1107

页数：14

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