TGF-β Induces Endometriotic Progression via a Noncanonical, KLF11-Mediated Mechanism

Luiz F. Correa, Correa LF, Zheng Y, Ye Zheng, Abigail A. Delaney, Delaney AA, Khan Z, Zaraq Khan, Chandra C. Shenoy, Gaurang S. Daftary, Daftary GS
Endocrinology · 2016 · vol. 157(9) , pp. 3332–3343 · doi:10.1210/en.2016-1194 · PMID:27384304 · W2472146617
Lab / animal OA: bronze CC0 ⤵ 18 in-corpus citations
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Transforming growth factor-beta induces endometriosis progression by epigenetically repressing CYP enzymes through a noncanonical, KLF11-mediated mechanism, which is reversed by TGFβR1 inhibition.

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Abstract

Endometriosis, a chronic disease of heterogeneous etiopathology affects 10% of young women and is characterized by ectopic implantation of endometrial cells. Growth and spread of endometriosis lesions involves biological interplay between intrinsic lesion-driven and extrinsic host-responsive mechanisms. We propose a role for TGFβ and its target transcription factor Krüppel-like factor 11 (KLF11) in mediating such mechanisms. Although TGFβ, a pleiotropic cytokine implicated in endometriosis potentially, mediates its pathological phenotypes, KLF11 is associated with endocrine and reproductive tract diseases, specifically progression of endometriosis. In Ishikawa cells, TGFβ1 treatment resulted in noncanonical SMAD-mediated transient up-regulation and sustained repression of KLF11. KLF11 recruits histone deacetylases to epigenetically repress multiple synthetic and metabolic cytochrome P450 (CYP) enzymes such as CYP3A4, which affects endometrial metabolism and pathophysiology. In contrast to KLF11, TGFβ1 treatment caused transient repression and sustained activation of CYP3A4 expression. CYP3A4 increased endometrial cell proliferation and was also increased in human endometriosis lesions compared with eutopic endometrium. To determine whether dysregulation of TGFβ/Klf11/Cyp3a signaling affected endometriotic progression, we treated wild-type control and Klf11-/- mice with a Tgfβ type 1 receptor inhibitor (TGFβR1I) that inhibits Tgfβ signaling upstream of the canonical Smad proteins or a combination of TGFβR1I and a histone acetyltransferase inhibitor that additionally inhibits Klf11 signaling. Disease progression and lesional Cyp3a expression was diminished in TGFβR1I-treated animals and more so in animals treated synergistically with TGFβR1I and histone acetyltransferase inhibitor. TGFβ and KLF11 thus mediate critical, translationally relevant host and lesion-driven responses that enable establishment and progression of endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Cell Cycle Proteins Endometriosis Repressor Proteins Transforming Growth Factor beta Animals Animals Apoptosis Regulatory Proteins Apoptosis Regulatory Proteins Cell Cycle Proteins Cell Cycle Proteins Cell Line Cell Line Cytochrome P-450 CYP3A Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System Cytochrome P-450 Enzyme System Cytochrome P-450 Enzyme System Disease Models, Animal Disease Models, Animal Disease Progression

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. Outer rings show 2-hop neighbours — papers reached through the immediate citers/citees. [ collapse to 1-hop ]

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