Histone Deacetylase 3 Governs β-Estradiol-ERα-Involved Endometrial Tumorigenesis via Inhibition of STING Transcription

Abstract

Purpose: The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. However, the contribution of acetylation involved in the regulation of STING to endometrial tumorigenesis remains unclear. Methods: We attempted to identify the key role of STING in endometrial carcinoma (EC) tissue and cell lines and explore its epigenetic regulation mechanism by HDACs that are critically involved in EC. We used IHC and qRT-PCR to detect the protein level and mRNA level of STING expression in endometrial carcinoma tissues, then explored the potential role of STING in tumor proliferation and apoptosis by CCK8 and flow cytometry, and identified the STING effect in the tumorigenicity by a mouse xenograft assay. We explored the possible relationship of acetylation alteration in STING regulation by ChIP analysis and Co-IP, and we knocked out STING in ECC1 and Ishikawa cells using CRISPR-Cas9 to further confirm the critical role of STING restoration induced by HDAC3 inhibitor RGFP-966 in the proliferation and apoptosis. Results: We found that STING expression was largely decreased and worked as an important regulator of cell proliferation and apoptosis; either activated or overexpressed STING, with both pharmacological and genetic approaches, largely blocked cell proliferation and induced apoptosis in EC. Moreover, STING expression was deregulated by both β-estradiol and HDAC3. Mechanically, we determined that HDAC3 can interact with β-estradiol-ERα and induce deacetylation of histone 3 lysine 4 at the STING promoter, thereby decreasing STING expression. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Conclusion: This study reveals a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα and provides a promising therapy (a combination of HDAC and STING) for combating endometrial cancer.

Aberrant expression of histone deacetylase 8 in endometriosis and its potential as a therapeutic target

“…86,87 Consequently, there is reason to believe that both HDAC2 and HDAC3 expression is reduced as endometriotic lesions become more fibrotic, especially in DE lesions as reported here, in particular given the report that both HDAC2 and HDAC3 are constitutively expressed in normal endometrium. 88 This may also be supported by the report that HDAC3 overexpression in conjunction with estrogen-ERα suppresses STING endometrial epithelial cells 89 yet STING is upregulated in ectopic endometrium. 90 Indeed, we found that culturing an endometrial epithelial cell line in high-stiff substrates resulted in downregulation of HDAC3, 91 which may account for reduced endometrial HDAC3 expression in infertile women with endometriosis.…”

“… 86 , 87 Consequently, there is reason to believe that both HDAC2 and HDAC3 expression is reduced as endometriotic lesions become more fibrotic, especially in DE lesions as reported here, in particular given the report that both HDAC2 and HDAC3 are constitutively expressed in normal endometrium. 88 This may also be supported by the report that HDAC3 overexpression in conjunction with estrogen‐ERα suppresses STING endometrial epithelial cells 89 yet STING is upregulated in ectopic endometrium. 90 …”

Emerging mechanisms and implications of cGAS-STING signaling in cancer immunotherapy strategies

“…In endometrial cancer, histone deacetylase HDAC3 interacts with β-estradiol-ERα and induces histone 3 lysine 4 deacetylation at the STING promoter, thus decreasing STING expression. Inhibiting HDAC3 increases STING expression and suppresses tumorigenesis 114 . A recent study has reported that protein arginine methyltransferase PRMT1 methylates cGAS at a conserved R133 residue, prevents cGAS dimerization, and inhibits cGAS/STING signaling in cancer cells.…”

HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling

“… 11 Many of these ISGs encode proteins with antiviral properties, 12 , 13 with some acting back on STING to further amplify its responses. 14 The molecules are thought to involve positive feedback regulation via STAT1 promoter binding, 14 ubiquitination, 15 sumoylation, 16 phosphorylation, 17 methylation, 18 or 19 acetylation of cGAS or STING itself.…”