Expression of Tribbles Pseudokinase 3 in Prostate Cancers and Its Roles in Cell Cycle Regulation

Tribbles Pseudokinase 3 (TRIB3) is a negative regulator of cellular signaling, particularly the PI3K-Akt and NF-κB pathways. Aberrant TRIB3 expressions have been reported in a number of cancers, but its role in tumor growth and progression remains controversial since both oncogenic and tumor suppressive activities have been reported. The goal of this study is to understand the roles of TRIB3 in prostate cancers through bioinformatic queries of public databases and experimental evaluations through gain-of-function and loss-of-function approaches. Here we report that there was increased TRIB3 gene expression with a Z-score over 2, relative to normal samples, in 26% of prostate cancers. Increased TRIB3 expression was associated with increased mutation counts and aneuploidy scores of prostate cancers. Increased TRIB3 expression was also associated with reduced progression-free or disease-free survival of prostate cancer patients. However, our experiments found that increased TRIB3 expression actually had an antiproliferative effect and increased cell cycle arrest at the G2/M phase. Depletion of the endogenous TRIB3 expression enhanced cell proliferation and reduced the level of Cdc25C phosphatase. Our results suggest that although TRIB3 expression was increased in prostate cancers in association with increased genomic instabilities, TRIB3 actually promoted cell cycle arrest and reduced tumor cell proliferation.