Divergent Modulation of Proteostasis in Prostate Cancer

Ballar Kırmızıbayrak P., Erbaykent Tepedelen B., Gözen O., Erzurumlu Y.

in: Proteostasis and Disease, Rosa Barrio,James D. Sutherland,Manuel S. Rodriguez, Editor, Springer, London/Berlin , Schwyz, pp.117-152, 2020

  • Publication Type: Book Chapter / Chapter Vocational Book
  • Publication Date: 2020
  • Publisher: Springer, London/Berlin 
  • City: Schwyz
  • Page Numbers: pp.117-152
  • Editors: Rosa Barrio,James D. Sutherland,Manuel S. Rodriguez, Editor
  • Bursa Uludag University Affiliated: Yes


Proteostasis regulates key cellular processes such as cell proliferation, differentiation, transcription, and apoptosis. The mechanisms by which proteostasis is regulated are crucial and the deterioration of cellular proteostasis has been significantly associated with tumorigenesis since it specifically targets key oncoproteins and tumor suppressors. Prostate cancer (PCa) is the second most common cause of cancer death in men worldwide. Androgens mediate one of the most central signaling pathways in all stages of PCa via the androgen receptor (AR). In addition to their regulation by hormones, PCa cells are also known to be highly secretory and are particularly prone to ER stress as proper ER function is essential. Alterations in various complex signaling pathways and cellular processes including cell cycle control, transcription, DNA repair, apoptosis, cell adhesion, epithelialmesenchymal transition (EMT), and angiogenesis are critical factors

influencing PCa development through key molecular changes mainly by posttranslational

modifications in PCa-related proteins, including AR, NKX3.1, PTEN, p53, cyclin D1, and

p27. Several ubiquitin ligases like MDM2, Siah2, RNF6, CHIP, and substrate-binding

adaptor SPOP; deubiquitinases such as USP7, USP10, USP26, and USP12 are just some of the modifiers involved in the regulation of these key proteins via ubiquitinproteasome

system (UPS). Some ubiquitin-like modifiers, especially SUMOs, have been also closely

associated with PCa. On the other hand, the proteotoxicity resulting from misfolded proteins and failure of ER adaptive capacity induce unfolded protein response (UPR) that is an indispensable signaling mechanism for PCa development. Lastly, ER-associated degradation (ERAD) also plays a crucial role in prostate tumorigenesis. In this section, the

relationship between prostate cancer and proteostasis will be discussed in terms of UPS, UPR, SUMOylation, ERAD, and autophagy.