HDAC inhibitor ITF2357 reduces resistance of mutant-KRAS non-small cell lung cancer to pemetrexed through a HDAC2/miR-130a-3p-dependent mechanism.

BACKGROUND: Histone deacetylases (HDAC) contribute to oncogenic program, pointing to their inhibitors as a potential strategy against cancers. We, thus, studied the mechanism of HDAC inhibitor ITF2357 in resistance of mutant (mut)-KRAS non-small cell lung cancer (NSCLC) to pemetrexed (Pem). METHODS: We first determined the expression of NSCLC tumorigenesis-related HDAC2 and Rad51 in NSCLC tissues and cells. Next, we illustrated the effect of ITF2357 on the Pem resistance in wild type-KARS NSCLC cell line H1299, mut-KARS NSCLC cell line A549 and Pem-resistant mut-KARS cell line A549R in vitro and in xenografts of nude mice in vivo. RESULTS: Expression of HDAC2 and Rad51 was upregulated in NSCLC tissues and cells. Accordingly, it was revealed that ITF2357 downregulated HDAC2 expression to diminish the resistance of H1299, A549 and A549R cells to Pem. HDAC2 bound to miR-130a-3p to upregulate its target gene Rad51. The in vitro findings were reproduced in vivo, where ITF2357 inhibited the HDAC2/miR-130a-3p/Rad51 axis to reduce the resistance of mut-KRAS NSCLC to Pem. CONCLUSION: Taken together, HDAC inhibitor ITF2357 restores miR-130a-3p expression by inhibiting HDAC2, thereby repressing Rad51 and ultimately diminishing resistance of mut-KRAS NSCLC to Pem. Our findings suggested HDAC inhibitor ITF2357 as a promising adjuvant strategy to enhance the sensitivity of mut-KRAS NSCLC to Pem.

Prenatal benzo[a]pyrene exposure impairs hippocampal synaptic plasticity and cognitive function in SD rat offspring during adolescence and adulthood via HDAC2-mediated histone deacetylation.

Benzo[a]pyrene (B[a]P) is a widespread carcinogenic pollutant in the environment. Although previous studies have demonstrated the neurodevelopmental toxicity of B[a]P, the precise mechanisms underlying the neurotoxic effects induced by prenatal B[a]P exposure remain largely unknown. In the present study, pregnant Sprague-Dawley (SD) rats were injected intraperitoneally with 0, 10, 20, or 40 mg/kg-bw of B[a]P for three consecutive days on embryonic days 17-19. The learning and memory abilities of offspring were determined by Morris Water Maze (MWM) test, while the number of dendritic branches and the density of dendritic spines in hippocampal CA1 and DG regions were evaluated by Golgi-Cox staining at PND 45 and PND 75. The mRNA expression of BDNF, PSD-95, and SYP in offspring hippocampus were detected by qRT-PCR, and the protein expression of BDNF, PSD-95, SYP, HDAC2, acH3K9, and acH3K14 were measured by Western blotting or immunohistochemistry. CHIP-PCR was performed to further detect the levels of acH3K9 and acH3K14 in the promoter regions of BDNF and PSD-95 genes. Our results showed that rats prenatally exposed to B[a]P exhibited impaired spatial learning and memory abilities and the number of dendritic branches and the density of dendritic spines in the hippocampal CA1 and DG regions were significantly reduced during adolescence and adulthood. The expression of HDAC2 protein was significantly upregulated, while acH3K9, acH3K14, BDNF, PSD-95, and SYP protein levels were significantly downregulated in the hippocampus of B[a]P- exposed rats. In addition, CHIP results showed that prenatal B[a]P exposure markedly decreased the level of acH3K9 and acH3K14 in the promoter region of BDNF and PSD-95 gene in the hippocampus of PND 45 and PND 75 offspring. All of the results suggest that prenatal B[a]P exposure impairs cognitive function and hippocampal synaptic plasticity of offspring in adolescence and adulthood, and HDAC2-mediated histone deacetylation plays a crucial role in these deficits.

Short-Chain Fatty Acids Attenuate Renal Fibrosis and Enhance Autophagy of Renal Tubular Cells in Diabetic Mice Through the HDAC2/ULK1 Axis.

BACKGRUOUND: This study investigated the effect of short-chain fatty acids (SCFAs) on diabetes in a mouse model. METHODS: Autophagy in Akita mice and streptozocin (STZ)-induced diabetic C57BL/6 mice was determined by Western blots and immunohistochemistry (IHC). Western blots, IHC, hematoxylin and eosin staining, Masson staining, periodic acid-Schiff staining, and picrosirius red staining were conducted to detect whether autophagy and renal function improved in Akita mice and STZ-induced diabetic C57BL/6 mice after treatment of SCFAs. Western blots, IHC, and chromatin immunoprecipitation were performed to determine whether SCFAs affected diabetic mice via the histone deacetylase (HDAC2)/unc-51 like autophagy activating kinase 1 (ULK1) axis. Diabetic mice with kidney-specific knockout of HDAC2 were constructed, and IHC, Masson staining, and Western blots were carried out to detect whether the deletion of endogenous HDAC2 contributed to the improvement of autophagy and renal fibrosis in diabetic mice. RESULTS: Reduced autophagy and severe fibrosis were observed in Akita mice and STZ-induced diabetic C57BL/6 mice. Increased autophagy and reduced renal cell fibrosis were found in SCFA-treated Akita diabetic mice and STZ-induced diabetic C57BL/6 mice. Diabetic mice treated with SCFAs had lower HDAC2 expression and more enriched binding of ULK1 promoter sequences to H3K27Ac. Endogenous knockout of HDAC2 caused enhanced autophagy and decreased renal fibrosis in diabetic mice treated with SCFAs. CONCLUSION: SCFAs enhanced autophagy of renal tubular cells and attenuated renal fibrosis in diabetic mice through the HDAC2/ULK1 axis.

Effects of dexmedetomidine on cognitive dysfunction and neuroinflammation via the HDAC2/HIF-1α/PFKFB3 axis in a murine model of postoperative cognitive dysfunction.

Inhibition of histone deacetylase (HDAC) may be a useful approach in the treatment of disorders characterized by cognitive dysfunction. Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has demonstrated neuroprotective effects. Here, we attempted to investigate the protective effects of DEX on postoperative cognitive dysfunction (POCD) involving HDAC2. Male C57BL/6 mice were selected to develop a POCD model, where HDAC2, HIF-1α, and PFKFB3 expression was quantified. DEX was administered before POCD modeling. Then the cognitive function of POCD mice was evaluated with the open field and Y-maze tests. Meanwhile, lipopolysaccharide (LPS) was employed to induce BV-2 microglial cells to simulate the inflammatory response. The contents of TNF-α, IL-6, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) in mouse serum and BV-2 cell supernatant. Abundant expression of HDAC2, HIF-1α, and PFKFB3 was confirmed in POCD mice (p < 0.05). Cognitive dysfunction in POCD mice could be alleviated following pharmacological inhibition of HDAC2 by FK228 (p < 0.05). Mechanistically, HDAC2 upregulated HIF-1α and PFKFB3 and promoted the secretion of inflammatory factors in LPS-exposed BV-2 cells (p < 0.05). DEX attenuated neuroinflammation and the resulting cognitive dysfunction by decreasing HDAC2 expression and HIF-1α-dependent PFKFB3 upregulation in POCD mice (p < 0.05). In conclusion, DEX-regulated HDAC2 may play an inhibitory role in mice with POCD through regulation of the HIF-1α/PFKFB3 axis.

HDAC2 Suppresses IL17A-Mediated Airway Remodeling in Human and Experimental Modeling of COPD.

BACKGROUND: Although airway remodeling is a central feature of COPD, the mechanisms underlying its development have not been fully elucidated. The goal of this study was to determine whether histone deacetylase (HDAC) 2 protects against cigarette smoke (CS)-induced airway remodeling through IL-17A-dependent mechanisms. METHODS: Sputum samples and lung tissue specimens were obtained from control subjects and patients with COPD. The relationships between HDAC2, IL-17A, and airway remodeling were investigated. The effect of HDAC2 on IL-17A-mediated airway remodeling was assessed by using in vivo models of COPD induced by CS and in vitro culture of human bronchial epithelial cells and primary human fibroblasts exposed to CS extract, IL-17A, or both. RESULTS: HDAC2 and IL-17A expression in the sputum cells and lung tissue samples of patients with COPD were associated with bronchial wall thickening and collagen deposition. Il-17a deficiency (Il-17a-/-) resulted in attenuation of, whereas Hdac2 deficiency (Hdac2+/-) exacerbated, CS-induced airway remodeling in mice. IL-17A deletion also attenuated airway remodeling in CS-exposed Hdac2+/- mice. HDAC2 regulated IL-17A production partially through modulation of CD4+ T cells during T helper 17 cell differentiation and retinoid-related orphan nuclear receptor γt in airway epithelial cells. In vitro, IL-17A deficiency attenuated CS-induced mouse fibroblast activation from Hdac2+/- mice. IL-17A-induced primary human fibroblast activation was at least partially mediated by autocrine production of transforming growth factor beta 1. CONCLUSIONS: These findings suggest that activation of HDAC2 and/or inhibition of IL-17A production could prevent the development of airway remodeling by suppressing airway inflammation and modulating fibroblast activation in COPD.