KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance

Jung-Yoon Yoo, Jung‐Yoon Yoo, Tae Hoon Kim, Asgerally T Fazleabas, Wilder A Palomino, Soo Hyun Ahn, Chandrakant Tayade, David P Schammel, Steven L Young, Jae-Wook Jeong, Bruce A Lessey
Scientific reports · 2017 · vol. 7(1) , pp. 6765 · doi:10.1038/s41598-017-04577-w · PMID:28754906 · PMC5533722 · W2737330582
article OA: gold CC0 ⤵ 65 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

KRAS activation and over-expression of SIRT1/BCL6 in eutopic endometrium contribute to endometriosis pathogenesis and progesterone resistance by suppressing GLI1 expression.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This study examined whether KRAS activation and SIRT1 overexpression occur in eutopic endometrium of women with endometriosis, and whether they relate to progesterone resistance and altered gene regulation. Using protein measurements (western blot, immunohistochemistry) in human endometrial tissue across menstrual phases and a mouse model with conditional KRAS activation in PGR-positive cells, the authors found higher KRAS and SIRT1 protein levels in endometriosis compared with controls, with KRAS and SIRT1 positively correlated. In the mouse model, progesterone receptor target genes (including Indian hedgehog pathway genes) were down-regulated, and ChIP/colocalization analyses showed SIRT1 and BCL6 binding to and suppressing the GLI1 promoter, while GLI1 expression was reduced in endometriosis samples; the paper’s limitation is that the data are primarily mechanistic and correlative between human protein expression and functional pathways in vivo models rather than establishing direct causality in humans. This paper is centrally about endometriosis — it links KRAS-driven SIRT1/BCL6 overexpression to progesterone resistance via GLI1 repression in eutopic endometrium.

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Abstract

Endometriosis is an inflammatory condition that is associated with progesterone resistance and cell proliferation, resulting in pain, infertility and pregnancy loss. We previously demonstrated phosphorylation of STAT3 in eutopic endometrium of infertile women with this disorder leading to over-expression of the oncogene BCL6 and stabilization of hypoxia-induced factor 1 alpha (HIF-1α). Here we report coordinated activation of KRAS and over-expression of Sirtuin 1 (SIRT1), a histone deacetylase and gene silencer, in the eutopic endometrium from women with endometriosis throughout the menstrual cycle. The mice with conditional activation of KRAS in the PGR positive cells reveal an increase of SIRT1 expression in the endometrium compared to control mice. The expression of progesterone receptor target genes including the Indian Hedgehog pathway genes are significantly down-regulated in the mutant mice. SIRT1 co-localizes with BCL6 in the nuclei of affected individuals and both proteins bind to and suppress the promoter of GLI1, a critical mediator of progesterone action in the Indian Hedgehog pathway, by ChIP analysis. In eutopic endometrium, GLI1 expression is reduced in women with endometriosis. Together, these data suggest that KRAS, SIRT1 and BCL6 are coordinately over-expressed in eutopic endometrium of women with endometriosis and likely participate in the pathogenesis of endometriosis.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Endometrium Proto-Oncogene Proteins c-bcl-6 Proto-Oncogene Proteins p21(ras) Sirtuin 1 Uterine Diseases Adolescent Adult Animals Cytokines Cytokines Disease Models, Animal Disease Progression Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Female

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