TY - JOUR
T1 - TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells
AU - Hernández-Quiles, Miguel
AU - Baak, Rosalie
AU - Orea-Soufi, Alba
AU - Borgman, Anouska
AU - den Haan, Suzanne
AU - Sobrevals Alcaraz, Paula
AU - Jongejan, Aldo
AU - van Es, Robert
AU - Velasco, Guillermo
AU - Vos, Harmjan
AU - Kalkhoven, Eric
N1 - Funding Information: This study was supported by grants from the European Union’s Horizon 2020 Marie Skłodowska-Curie Innovative Training Network, TRAIN (project No. 721532) and a combined Diabetes Breakthrough grant from the Dutch Diabetes Research Foundation and The Netherlands Organisation for Health Research and Development (ZonMW; project No. 459001006). Publisher Copyright: © 2022 by the authors.
PY - 2022/9/11
Y1 - 2022/9/11
N2 - 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.
AB - 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.
KW - MLL–WRAD complex
KW - PPARγ
KW - Tribbles
KW - breast cancer
KW - epigenetics
UR - http://www.scopus.com/inward/record.url?scp=85138427936&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms231810535
DO - https://doi.org/10.3390/ijms231810535
M3 - Article
C2 - 36142452
SN - 1661-6596
VL - 23
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 18
M1 - 10535
ER -