KLFII Epigenetically Regulates Glycodelin-A, a Marker of Endometrial Biology Via Histone-Modifying Chromatin Mechanisms

Tabbaa, Zaid M.; Zheng, Ye; Daftary, Gaurang S.

doi:10.1177/1933719113503407

Cited by 12 publications

(11 citation statements)

References 56 publications

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“…KLF10 has been previously shown to interact with the JARID1B/KDM5B histone demethylase corepressor [ 45 ]. KLF10 shares an N-terminal repressor domain with KLF11 that binds to SIN3A/HDAC corepressor to affect target gene regulation [ 31 , 46 – 48 ]. We show here for the first time that as with KLF11, this region in KLF10 is critical for epigenetic repression of CD154.…”

Section: Discussionmentioning

confidence: 99%

KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis

Delaney

Khan

Zheng

et al. 2016

Biology of Reproduction

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Endometriosis is a highly prevalent, chronic, heterogeneous, fibro-inflammatory disease that remains recalcitrant to conventional therapy. We previously showed that loss of KLF11, a transcription factor implicated in uterine disease, results in progression of endometriosis. Despite extensive homology, co-expression, and human disease association, loss of the paralog Klf10 causes a unique inflammatory, cystic endometriosis phenotype in contrast to fibrotic progression seen with loss of Klf11. We identify here for the first time a novel role for KLF10 in endometriosis. In an animal endometriosis model, unlike wild-type controls, Klf10−/− animals developed cystic lesions with massive immune infiltrate and minimal peri-lesional fibrosis. The Klf10−/− disease progression phenotype also contrasted with prolific fibrosis and minimal immune cell infiltration seen in Klf11−/− animals. We further found that lesion genotype rather than that of the host determined each unique disease progression phenotype. Mechanistically, KLF10 regulated CD40/CD154-mediated immune pathways. Both inflammatory as well as fibrotic phenotypes are the commonest clinical manifestations in chronic fibro-inflammatory diseases such as endometriosis. The complementary, paralogous Klf10 and Klf11 models therefore offer novel insights into the mechanisms of inflammation and fibrosis in a disease-relevant context. Our data suggests that divergence in underlying gene dysregulation critically determines disease-phenotype predominance rather than the conventional paradigm of inflammation being precedent to fibrotic scarring. Heterogeneity in clinical progression and treatment response are thus likely from disparate gene regulation profiles. Characterization of disease phenotype-associated gene dysregulation offers novel approaches for developing targeted, individualized therapy for recurrent and recalcitrant chronic disease.

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Section: Discussionmentioning

confidence: 99%

KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis

Delaney

Khan

Zheng

et al. 2016

Biology of Reproduction

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“…Real-time PCR was performed using commercial primers for COL1A1 (Qiagen) and a panel of housekeeping controls: glyceraldehyde-3phosphate dehydrogenase (GAPDH/Gapdh), beta-2-microglobulin (B2M/B2m), and hypoxanthine phosphoribosyltransferase 1 (HPRT1/Hprt1) (Qiagen). PCR optimization and controls were performed as described previously [16,19,20]. Quantitative PCR reactions were performed using the IQ-SYBR Green Supermix (Bio-Rad) in a PikoReal96 Real-Time PCR System (Thermo-Scientific).…”

Section: Zheng Et Almentioning

confidence: 99%

“…Chromatin immunoprecipitation (ChIP) was performed using E-Z ChIP per kit protocol (Millipore) as described [16,[19][20][21]. Briefly, 2 310 6 cells were lysed and sonicated to generate 200 ; 600 bp fragments.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis1

Zheng

Khan

Zanfagnin

et al. 2016

Biology of Reproduction

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Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases.

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“…Other previous studies have postulated that the activation of PAEP expression is associated with the transcription factors GATA-binding protein 3 (GATA3), the microphthalmia-associated transcriptions factor (MITF) and the specific protein1 (Sp1) (30-32). Only the Krüppel-like transcription factor11 (KLF11) has been assumed to suppress glycodelin expression (33).…”

Section: Introductionmentioning

confidence: 99%

Pathways regulating the expression of the immunomodulatory protein glycodelin in non‑small cell lung cancer

et al. 2018

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Glycodelin [gene name, progesterone associated endometrial protein (PAEP)] was initially described as an immune system modulator in reproduction. Today, it is also known to be expressed in several types of cancer, including non-small cell lung cancer (NSCLC). In this cancer type, the feasibility of its usage as a follow-up biomarker and its potential role as an immune system modulator were described. It is assumed that NSCLC tumours secrete glycodelin to overcome immune surveillance. Therefore, targeting glycodelin might be a future approach with which to weaken the immune system defence of NSCLC tumours. In this context, it is important to understand the regulatory pathways of PAEP/glycodelin expression, as these are mostly unknown so far. In this study, we analysed the influence of several inducers and of their downstream pathways on PAEP/glycodelin expression in a human lung adenocarcinoma carcinoma (ADC; H1975) and a human lung squamous cell carcinoma (SQCC) cell line (2106T). PAEP/glycodelin expression was notably stimulated by the canonical transforming growth factor (TGF)-β pathway in SQCC cells and the PKC signalling cascade in both cell lines. The PI3K/AKT pathway inhibited PAEP/glycodelin expression in the ADC cells and an antagonizing role towards the other investigated signalling cascades is suggested herein. Furthermore, the mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinases (ERK) pathway was, to a lesser extent, found to be associated with increased PAEP/glycodelin amounts. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), MEK/ERK pathway and TGF-β are targets of NSCLC drugs that are already approved or are currently under investigation. On the whole, the findings of this study provide evidence that inhibiting these targets affects the expression of glycodelin and its immunosuppressive effect in NSCLC tumours. Moreover, understanding the regulation of glycodelin expression may lead to the development of novel therapeutic approaches with which to weaken the immune system defence of NSCLC tumours in the future.

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KLFII Epigenetically Regulates Glycodelin-A, a Marker of Endometrial Biology Via Histone-Modifying Chromatin Mechanisms

Cited by 12 publications

References 56 publications

KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis

KLF10 Mediated Epigenetic Dysregulation of Epithelial CD40/CD154 Promotes Endometriosis

Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis1

Pathways regulating the expression of the immunomodulatory protein glycodelin in non‑small cell lung cancer

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