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

Tobias Furlan,Alexander Kirchmair,Natalie Sampson,Martin Puhr,Martina Gruber,Zlatko Trajanoski,Frédéric R Santer,Walther Parson,Florian Handle,Zoran Culig

doi:10.1016/j.ajpath.2021.02.017

Tobias Furlan, Alexander Kirchmair + Show 8 more

Open Access

https://doi.org/10.1016/j.ajpath.2021.02.017

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Journal: The American Journal of Pathology	Publication Date: Mar 8, 2021
Citations: 16	License type: cc-by

Affiliation: Universität Innsbruck

Abstract

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 castration-resistant 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.

Highlights

Patients with advanced prostate cancer are frequently treated with the antiandrogen enzalutamide
Viability was strongly reduced in all cell lines upon treatment with the EP300/CREBBP inhibitors, as determined by a real-time cell viability assay (Figure 1B)
EP300 was identified as a target in chemotherapy-resistant Prostate cancer (PCa) cells.[13]

Summary

Introduction

Patients with advanced prostate cancer are frequently treated with the antiandrogen enzalutamide. EP300/CREBBP inhibitors led to the same inhibition of androgen receptor activity in enzalutamide-resistant and -sensitive cells. The current data show that EP300/CREBBP inhibitors affect the MYC/ribosomal protein axis in enzalutamide-resistant cells and may have promising therapeutic implications. For recurrent PCa, androgen deprivation therapy via chemical or surgical castration remains the current standard-of-care treatment.[1] the therapy is initially effective, the development of castration-resistant PCa is nearly always inevitable. In this case, blockade of the androgen receptor (AR) is used, commonly with the antiandrogen enzalutamide. The histone acetyl transferase (HAT) EP300 (P300) and its paralogue CREBBP (CBP) are involved in several signaling pathways associated with therapy resistance.[4]

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