The Role of Alcohol-Induced Golgi Fragmentation for Androgen Receptor Signaling in Prostate Cancer

Abstract

Multiple epidemiologic observations and meta-analysis clearly indicate the link between alcohol abuse and the incidence and progression of prostate cancer; however, the mechanism remains enigmatic. Recently, it was found that ethanol (EtOH) induces disorganization of the Golgi complex caused by impaired function of the largest Golgi matrix protein, giantin (GOLGB1), which, in turn, alters the Golgi docking of resident Golgi proteins. Here, it is determined that in normal prostate cells, histone deacetylase 6 (HDAC6), the known regulator of androgen receptor (AR) signaling, localizes in the cytoplasm and nucleus, while its kinase, glycogen synthase kinase β (GSK3β), primarily resides in the Golgi. Progression of prostate cancer is accompanied by Golgi scattering, translocation of GSK3β from the Golgi to the cytoplasm, and the cytoplasmic shift in HDAC6 localization. Alcohol dehydrogenase-generated metabolites induces Golgi disorganization in androgen-responsive LNCaP and 22Rv1 cells, facilitates tumor growth in a mouse xenograft model and activates anchorage-independent proliferation, migration, and cell adhesion. EtOH-treated cells demonstrate reduced giantin and subsequent cytoplasmic GSK3β; this phenomenon was validated in giantin-depleted cells. Redistribution of GSK3β to the cytoplasm results in phosphorylation of HDAC6 and its retention in the cytoplasm, which, in turn, stimulates deacetylation of HSP90, AR import into the nucleus, and secretion of prostate-specific antigen (PSA). Finally, the relationship between Golgi morphology, HDAC6 cytoplasmic content, and clinicopathologic features was assessed in human prostate cancer patient specimens with and without a history of alcohol dependence. This study demonstrates the importance of alcohol-induced Golgi fragmentation in the activation of AR-mediated proliferation.

The Great Escape: how phosphatidylinositol 4-kinases and PI4P promote vesicle exit from the Golgi (and drive cancer)

“…In some tumours the changes to Golgi trafficking, signalling and morphology (28)(29)(30)(31)(32)(33)(34)(35) can be so pronounced that the term "onco-Golgi" has been proposed to capture its altered status in malignant disease (36). Relevant to this concept, gene mutations that lead to increased expression of Golgi-targeted PI4P binding proteins or PI 4-kinases can be associated with a distended Golgi morphology (37) and the anterograde trafficking of proteins (38)(39)(40)(41) that drive angiogenesis (42,43), tumour invasion (44)(45)(46)(47) and metastasis (48)(49)(50)(51).…”

Post-ER Stress Biogenesis of Golgi Is Governed by Giantin

“…In addition, the induction of ER stress by the Arf1 mutant results in the relocation of GRASP55 dimer to the ER and its subsequent monomerization [111]. Notably, in different cells and organs, EtOH-induced Golgi disorganization was associated with giantin de-dimerization [13,52]. In our preliminary screening, treatment of prostate cells with the ER stress inducer, Thapsigargin, results in Golgi fragmentation, which again was accompanied by the loss of giantin dimer (manuscript in preparation).…”

The GRASP domain in Golgi Reassembly and Stacking Proteins: differences and similarities between lower and higher Eukaryotes

“…While GRASP65 is located mainly in the cis part of the Golgi, GRASP55 is present in the medial and trans faces [6,7]. These unique localizations of both GRASPs have been explored as Golgi markers for co-localization experiments in several manuscripts [12,13].…”