MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas
Azna Zuberi, Yongchao Huang, Ariel J. Dotts, Helen Wei, John S. Coon V, Shimeng Liu, Takashi Iizuka, Olivia Wu, Olivia Sotos, Priyanka Saini, Debabrata Chakravarti, Thomas G. Boyer, Yang Dai, Serdar E. Bulun, Ping Yin
Azna Zuberi, Yongchao Huang, Ariel J. Dotts, Helen Wei, John S. Coon V, Shimeng Liu, Takashi Iizuka, Olivia Wu, Olivia Sotos, Priyanka Saini, Debabrata Chakravarti, Thomas G. Boyer, Yang Dai, Serdar E. Bulun, Ping Yin
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Research Article Metabolism Reproductive biology

MED12 mutation activates the tryptophan/kynurenine/AHR pathway to promote growth of uterine leiomyomas

Abstract

Uterine leiomyomas cause heavy menstrual bleeding, anemia, and pregnancy loss in millions of women worldwide. Driver mutations in the transcriptional mediator complex subunit 12 (MED12) gene in uterine myometrial cells initiate 70% of leiomyomas that grow in a progesterone-dependent manner. We showed a distinct chromatin occupancy landscape of MED12 in mutant MED12 (mut-MED12) versus WT-MED12 leiomyomas. Integration of cistromic and transcriptomics data identified tryptophan 2,3-dioxygenase (TDO2) as the top mut-MED12 target gene that was significantly upregulated in mut-MED12 leiomyomas when compared with adjacent myometrium and WT-MED12 leiomyomas. TDO2 catalyzes the conversion of tryptophan to kynurenine, an aryl hydrocarbon receptor (AHR) ligand that we confirmed to be significantly elevated in mut-MED12 leiomyomas. Treatment of primary mut-MED12 leiomyoma cells with tryptophan or kynurenine stimulated AHR nuclear translocation, increased proliferation, inhibited apoptosis, and induced AHR-target gene expression, whereas blocking the TDO2/kynurenine/AHR pathway by siRNA or pharmacological treatment abolished these effects. Progesterone receptors regulated the expression of AHR and its target genes. In vivo, TDO2 expression positively correlated with the expression of genes crucial for leiomyoma growth. In summary, activation of the TDO2/kynurenine/AHR pathway selectively in mut-MED12 leiomyomas promoted tumor growth and may inform the future development of targeted treatments and precision medicine.

Authors

Azna Zuberi, Yongchao Huang, Ariel J. Dotts, Helen Wei, John S. Coon V, Shimeng Liu, Takashi Iizuka, Olivia Wu, Olivia Sotos, Priyanka Saini, Debabrata Chakravarti, Thomas G. Boyer, Yang Dai, Serdar E. Bulun, Ping Yin

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Figure 1

RNA-Seq analysis identifies mRNA expression differences between WT- and mut-MED12 LM and adjacent MyoF.

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RNA-Seq analysis identifies mRNA expression differences between WT- and ...
(A) Gene expression in G44D mut-MED12 LM (n = 6), WT-MED12 LM (n = 4), and their matched MyoF (n = 10) tissues was examined by unsupervised PCA. L, LM; M, MyoF. (B and C) MA (log2 fold change and means average) plots and heatmap showing differences in gene expression (up- and downregulated) in LM versus matched MyoF tissues. Differential gene expression was determined using a cutoff of Padj < 0.05. Gene expression levels relative to the mean expression are shown as row Z scores. (D) Venn diagrams showing unique or shared differentially expressed genes (DEGs) between mut- and WT-MED12 LM versus their matched MyoF (fold change >1.5, Padj < 0.05). T, total. (E–G) Top 10 enriched KEGG pathways in DEGs uniquely present in mut-MED12 LM versus matched MyoF (E) and in DEGs shared between mut- and WT-MED12 LM versus their matched MyoF (F), and 6 enriched pathways in DEGs uniquely present in WT-MED12 LM versus matched MyoF (G).