Histone acetyltransferase inhibitors(Boehringer Ingelheim/ Epizyme)

Middle ear cholesteatoma (Cholesteatoma) consists of proliferative epithelial cells. In the previous study, we demonstrated that histone H3 acetylation at lysine 27 (H3K27ac), associated with high transcriptional activation, was accumulated in the Cholesteatoma. In this study, we firstly investigated the expression of H3K27ac and histone acetyltransferase, p300 in human Cholesteatoma tissues. And then, we investigated the effects of a p300 inhibitor, C646, against Cholesteatoma growth.

Immunohistochemical analysis was demonstrated in the human Cholesteatoma specimens using anti-p300 and anti-H3K27ac antibodies and in the KGF-induced Cholesteatoma mouse model after p300 inhibitor administration using anti-p300, anti-H3K27ac, and anti-Ki67 antibodies.

The expression levels of p300 were significantly increased and colocalized with H3K27ac in the human Cholesteatoma specimens. Moreover, C646 decreased proliferative activities of Cholesteatoma cells in the KGF-induced Cholesteatoma mouse model.

We demonstrated that inhibition of the H3K27ac may be a potential treatment strategy for Cholesteatoma from a new perspective.

Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer (BC). Some potential molecular targets have been identified, and miR-105-5p was found to be abnormally expressed in TNBC tissues.

The objective of this study was to probe the effect of miR-105-5p on TNBC via FOXG1/HDAC2-mediated acetylation.

An animal model of TNBC was established by injecting BC cells into the axillary area of nude mice. The levels of miR-105-5p, FOXG1, HDAC2, Bcl-2, Bax, and Ki67 were detected via RT‒qPCR, Western blotting and immunohistochemistry. Flow cytometry, CCK-8, Transwell and colony formation assays were used to measure apoptosis, proliferation and migration, respectively. Total histone acetylation levels were measured by ELISA. The binding of FOXG1 to HDAC2 was detected by co-immunoprecipitation. The binding relationship between miR-105-5p and FOXG1 was verified using a dual-luciferase reporter gene assay.

In this study, miR-105-5p and HDAC2 were highly expressed in the MDA-MB-231 and BT-549 BC cell lines, whereas FOXG1 was expressed at low levels. The inhibition of miR-105-5p inhibited the proliferation and migration of MDA-MB-231 and BT-549 cells and promoted their apoptosis. Bioinformatics analysis revealed that miR-105-5p and FOXG1 had a negative targeting regulatory relationship. FOXG1 overexpression had a similar effect on cancer cells as the inhibition of miR-105-5p. Moreover, experiments revealed that FOXG1 and HDAC2 could bind to each other and that HDAC2 overexpression or treatment with the histone acetyltransferase inhibitor Garcinol weakened the effect of FOXG1 overexpression. In addition, FOXG1 knockdown inhibited the effect of the miR-105-5p inhibitor, while Garcinol treatment further enhanced the effect of FOXG1 knockdown, inhibited histone acetylation, promoted the proliferation and migration of cancer cells, and inhibited apoptosis. Moreover, the in vivo results confirmed the in vitro results.

miR-105-5p promotes HDAC2 expression by reducing FOXG1, inhibits histone acetylation, and aggravates the malignant biological behavior of TNBC cells.