TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells

Abstract

Aberrant expression or activity of proteins are amongst the best understood mechanisms that can drive cancer initiation and progression, as well as therapy resistance. TRIB3, a member of the Tribbles family of pseudokinases, is often dysregulated in cancer and has been associated with breast cancer initiation and metastasis formation. However, the underlying mechanisms by which TRIB3 contributes to these events are unclear. In this study, we demonstrate that TRIB3 regulates the expression of PPARγ, a transcription factor that has gained attention as a potential drug target in breast cancer for its antiproliferative actions. Proteomics and phosphoproteomics analyses together with classical biochemical assays indicate that TRIB3 interferes with the MLL complex and reduces MLL-mediated H3K4 trimethylation of the PPARG locus, thereby reducing PPARγ mRNA expression. Consequently, the overexpression of TRIB3 blunts the antiproliferative effect of PPARγ ligands in breast cancer cells, while reduced TRIB3 expression gives the opposite effect. In conclusion, our data implicate TRIB3 in epigenetic gene regulation and suggest that expression levels of this pseudokinase may serve as a predictor of successful experimental treatments with PPARγ ligands in breast cancer.

Analysis of endoplasmic reticulum stress-related gene signature for the prognosis and pattern in diffuse large B cell lymphoma

“…Compared with noncancerous tissues, TRIB3 expression was markedly increased in DLBCL patients, particularly in the ABC subtype and later stages, suggesting that TRIB3 may play a carcinogenic role in DLBCL 56 – 59 . As a member of the mammalian pseudokinase tribbles family, TRIB3 can interfere with a lot of proteins, such as kinase-dependent proteins, transcription factors, and ubiquitin ligases 60 , 61 .…”

PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation

“…The overexpression of TRIB3, a member of the Tribbles family of pseudokinases, blunts the antiproliferative effect of PPARγ ligands in breast cancer cells via the H3K4 trimethylation of the PPARG locus, which reduces PPARγ expression. Accordingly, the expression levels of TRIB3 may predict the efficacy of PPARγ ligand treatment in breast cancer [28]. Activated PPARγ has exhibited some potential in the treatment of central nervous system (CNS) diseases in preclinical models.…”