Endoplasmic reticulum stress downregulates c-MYC expression through proteasomal degradation in prostate cancer cells

Prostate cancer (PCa) is the most prevalent non-cutaneous cancer and second leading cause of cancer-related death among men in Western countries. Knowledge of its underlying molecular mechanism is necessary to characterise new therapeutic targets aimed at improving both diagnosis and treatment. The unfolded protein response (UPR) is a homeostatic mechanism activated by endoplasmic reticulum (ER) stress. Cancer cells evoke the UPR in order to cope with a range of cytotoxic conditions and promote cell survival. However, if the stress is not resolved, UPR pathways can switch to pro-apoptotic signalling. The oncoprotein c-MYC, one of the most frequently dysregulated genes in all human cancers, including PCa, has recently been mechanistically linked to the UPR. In this study, we investigated the interplay between UPR activation and c-MYC expression in PCa cells. We found that ER stress induced significant depletion in c-MYC protein expression, which was a result of proteasomal degradation. These effects appeared in parallel to UPR activation, examined at both mRNA and protein level, thus suggesting canonical UPR signalling pathway involvement. Silencing of PERK resulted in partial c-MYC recovery, indicating that the PERK branch of the UPR signals for c-MYC degradation under stress. c-MYC and XBP1s overexpression and knockdown experiments resulted in little effect under stressed and non-stressed conditions in PCa, despite recent literature reporting transcriptional activation of c-MYC by XBP1s. Previous publications show MYC regulation of the UPR, thus taken together with data in this study, a feedback loop between c-MYC and the UPR is proposed, offering opportunities for future therapeutic targeting.