Histone deacetylases meet microRNA-associated MMP-9 expression regulation in glucocorticoid-sensitive and -resistant cell lines

Abstract

Glucocorticoids are largely used in the treatment of inflammatory pathologies and/or hematological malignancies and regulate the expression of a variety of genes involved in inflammation or metastasis such as matrix metalloproteinases (MMP). Long-term exposure to glucocorticoids can result in failure of responsiveness, which is often associated with an unwanted gene expression. Epigenetic mechanisms are involved in gene expression modulated after development of glucocorticoid resistance but how these mechanisms take place must be further studied. The effects of HDAC inhibitors (HDACi) in a context of glucocorticoid resistance are still not well understood and need to be further investigated. We hypothesized that acquired glucocorticoid resistance associated to HDACi could disturbs epigenetic landscape, especially miR expression, leading to a modulation of MMP-9 gene expression and/or protein secretion, described as largely involved in bone remodeling and tumor invasion in multiple myeloma. To this aim, we used sensitive RPMI-8226 cell line and its dexamethasone- and methylprednisolone-resistant derivatives. The resistant cell lines displayed an 'open chromatin' and an MMP-9 overexpression comparatively to the sensitive cell line. HDACi treatment with MS-275 increased even more MMP-9 overexpression not only at an mRNA level but also at the protein level. We showed that MMP-9 expression regulation was not directly linked with HAT/HDAC balance alterations but rather with the deregulation of MMP-9-targeting miRs. Then, we first demonstrated that miR‑149 downregulation was directly involved in the MMP-9 overexpression following a chronic glucocorticoid exposure and that MS-275 could amplify this overexpression by inhibition of miR‑149 expression and miR‑520c overexpression. Taken together, these results indicate that the use of HDACi in a context of acquired glucocorticoid resistance could modify the epigenetic landscape, highlighting the importance of taking the glucocorticoid response status into consideration in treatment with HDACi.

MMP-9-Related microRNAs as Prognostic Markers for Hemorrhagic Transformation in Cardioembolic Stroke Patients

“…We further identified a link between miR-3123 and risk of HT in patients with cardioembolic stroke. Although experiments have suggested no relationship between miR-3123 levels and MMP-9 expression (36), our in silico tests predict it as a regulator of this enzyme. Future studies should explore this possibility further.…”

“…Interestingly, miR-21-5p did not emerge from our in silico screening. Nevertheless, we chose to include it because MMP-9 is regulated at stages other than transcription (28, 36), and it may regulate two MMP inhibitors (32, 37).…”

HDAC3-mediated silencing of miR-451 decreases chemosensitivity of patients with metastatic castration-resistant prostate cancer by targeting NEDD9

“… 27 , 28 Recently, HDACs have been shown to be one of the most important epigenetic factors governing gene expression, and they regulate various pathological processes, including chemoresistance, through transcriptional regulation of genes. 29 – 32 Accordingly, treatment with an HDAC inhibitor efficiently suppressed cell growth of prostate cancer lines through post-transcriptional upregulation of miR-320a that was correlated with prostate cancer prognosis. 33 Furthermore, miR-320a inhibition significantly abrogated the growth suppression induced by HDAC inhibitor treatment.…”

Variation of the epidermal expression of glucocorticoid receptor‐beta as potential predictive marker of bullous pemphigoid outcome

“…In our group, we observed an increased expression of the neutrophil chemoattractant IL‐8 using a dexamethasone‐resistant blood cell line with an increased GRβ/GRα ratio compared to the sensitive cell line (data not shown). In peripheral neutrophils from patients with COPD, GRβ expression has been associated with an increase of MMP‐9 expression, a protease also increased in the serum of patients with BP with relapse, and which is upregulated in glucocorticoid‐resistant cell lines . Thus, in addition to the reduced anti‐inflammatory response to corticosteroids, an increased ratio of GRβ/GRα may alter the pattern of inflammatory molecules in patients with BP at risk of relapse.…”