Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3584 Utrecht, CG, The Netherlands.
Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, 28040 Madrid, Spain.
Int J Mol Sci. 2022 Sep 11;23(18):10535. doi: 10.3390/ijms231810535.
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 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.
蛋白质的异常表达或活性是驱动癌症发生和进展以及治疗耐药性的最被理解的机制之一。TRIB3 是 Tribbles 家族的一种伪激酶成员，在癌症中经常失调，并且与乳腺癌的起始和转移形成有关。然而，TRIB3 促进这些事件的潜在机制尚不清楚。在这项研究中，我们证明 TRIB3 调节 PPARγ 的表达，PPARγ 作为转录因子，因其在乳腺癌中的抗增殖作用而受到关注，是一种潜在的药物靶点。蛋白质组学和磷酸化蛋白质组学分析以及经典生化测定表明，TRIB3 干扰 MLL 复合物并降低 MLL 介导的 基因座上的 H3K4 三甲基化，从而降低 PPARγ mRNA 的表达。因此，TRIB3 的过表达会削弱 PPARγ 配体在乳腺癌细胞中的抗增殖作用，而 TRIB3 表达的降低则会产生相反的效果。总之，我们的数据表明 TRIB3 参与了表观遗传基因调控，并表明该伪激酶的表达水平可能可作为乳腺癌中用 PPARγ 配体进行成功实验治疗的预测因子。
