JNK signaling-dependent regulation of histone acetylation are involved in anacardic acid alleviates cardiomyocyte hypertrophy induced by phenylephrine

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetyltransferase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the related upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling pathway in cardiac hypertrophy induced by PE. The mice cardiomyocyte hypertrophy model was successfully established by treating cells with PE in vitro. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9ac hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiomyocyte hypertrophy. In particular, AA inhibits the effects of JNK signaling on HATs-mediated histone acetylation, and could therefore be used to prevent and treat pathological cardiac hypertrophy.

Curcumin, an Inhibitor of p300-HAT Activity, Suppresses the Development of Hypertension-Induced Left Ventricular Hypertrophy with Preserved Ejection Fraction in Dahl Rats

We found that curcumin, a p300 histone acetyltransferase (HAT) inhibitor, prevents cardiac hypertrophy and systolic dysfunction at the stage of chronic heart failure in Dahl salt-sensitive rats (DS). It is unclear whether curcumin suppresses the development of hypertension-induced left ventricular hypertrophy (LVH) with a preserved ejection fraction. Therefore, in this study, we randomized DS (n = 16) and Dahl salt-resistant (DR) rats (n = 10) at 6 weeks of age to either curcumin or vehicle groups. These rats were fed a high-salt diet and orally administrated with 50 mg/kg/d curcumin or its vehicle for 6 weeks. Both curcumin and vehicle treatment groups exhibited similar degrees of high-salt diet-induced hypertension in DS rats. Curcumin significantly decreased hypertension-induced increase in posterior wall thickness and LV mass index, without affecting the systolic function. It also significantly reduced hypertension-induced increases in myocardial cell diameter, perivascular fibrosis and transcriptions of the hypertrophy-response gene. Moreover, it significantly attenuated the acetylation levels of GATA4 in the hearts of DS rats. A p300 HAT inhibitor, curcumin, suppresses the development of hypertension-induced LVH, without affecting blood pressure and systolic function. Therefore, curcumin may be used for the prevention of development of LVH in patients with hypertension.

Radiation-induced reprogramming drives glioma vascular transdifferentiation and tumor recurrence

Radiation-resistant glioma cells exhibit phenotypic plasticity leading to aggressive tumor recurrence. However, the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in proportions and functional states of glioma cells allowing for acquisition of vascular- and mesenchymal-like phenotypes. The primary phenotypic switch induced by radiation is transdifferentiation to endothelial-like and pericyte-like cells. In turn, the transdifferentiated cells promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation reprograms glioma cells driving vascular transdifferentiation and tumor recurrence, and highlights P300 HAT inhibitor as a potential therapeutic target for preventing GBM relapse.

Garcinol—A Natural Histone Acetyltransferase Inhibitor and New Anti-Cancer Epigenetic Drug

Garcinol extracted from Garcinia indica fruit peel and leaves is a polyisoprenylated benzophenone. In traditional medicine it was used for its antioxidant and anti-inflammatory properties. Several studies have shown anti-cancer properties of garcinol in cancer cell lines and experimental animal models. Garcinol action in cancer cells is based on its antioxidant and anti-inflammatory properties, but also on its potency to inhibit histone acetyltransferases (HATs). Recent studies indicate that garcinol may also deregulate expression of miRNAs involved in tumour development and progression. This paper focuses on the latest research concerning garcinol as a HAT inhibitor and miRNA deregulator in the development and progression of various cancers. Garcinol may be considered as a candidate for next generation epigenetic drugs, but further studies are needed to establish the precise toxicity, dosages, routes of administration, and safety for patients.

Anacardic acid protects against phenylephrine-induced mouse cardiac hypertrophy through JNK signaling-dependent regulation of histone acetylation

Cardiac hypertrophy is a complex process induced by the activation of multiple signaling pathways. We previously reported that anacardic acid (AA), a histone acetylase (HAT) inhibitor, attenuates phenylephrine (PE)-induced cardiac hypertrophy by downregulating histone H3 acetylation at lysine 9 (H3K9ac). Unfortunately, the upstream signaling events remained unknown. The mitogen-activated protein kinase (MAPK) pathway is an important regulator of cardiac hypertrophy. In this study, we explored the role of JNK/MAPK signaling in cardiac hypertrophy. A mouse model of cardiomyocyte hypertrophy was successfully established in vitro using PE. This study showed that p-JNK directly interacts with HATs (P300 and P300/CBP-associated factor, PCAF) and alters H3K9ac. In addition, both the JNK inhibitor SP600125 and the HAT inhibitor AA attenuated p-JNK overexpression and H3K9 hyperacetylation by inhibiting P300 and PCAF during PE-induced cardiomyocyte hypertrophy. Moreover, we demonstrated that both SP600125 and AA attenuate the overexpression of cardiac hypertrophy-related genes (MEF2A, ANP, BNP, and β-MHC), preventing cardiomyocyte hypertrophy and dysfunction. These results revealed a novel mechanism through which AA might protect mice from PE-induced cardiac hypertrophy. In particular, AA inhibits the effects of JNK signaling on HAT-mediated histone acetylation, and could therefore be used to prevent and treat hypertrophic cardiomyopathy.

Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract

Diabetic cataracts can occur at an early age, causing visual impairment or blindness. The detailed molecular mechanisms of diabetic cataract formation remain incompletely understood, and there is no well-documented prophylactic agent. Galactose-fed rats and ex vivo treatment of lenses with galactose are used as models of diabetic cataract. To assess the role of histone acetyltransferases, we conducted cataract prevention screening with known histone acetyltransferase (HAT) inhibitors. Ex vivo treatment with a HAT inhibitor strongly inhibited the formation of lens turbidity in high-galactose conditions, while addition of a histone deacetylase (HDAC) inhibitor aggravated turbidity. We conducted a microarray to identify genes differentially regulated by HATs and HDACs, leading to discovery of a novel cataract causative factor, Plk3. Plk3 mRNA levels correlated with the degree of turbidity, and Plk3 inhibition alleviated galactose-induced cataract formation. These findings indicate that epigenetically controlled Plk3 influences cataract formation. Our results demonstrate a novel approach for prevention of diabetic cataract using HAT and Plk3 inhibitors.