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

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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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