Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling

Wang, Jiaojiao; Liu, Zhiping; Feng, Xiaohai; Gao, Si; Xu, Suowen; Liu, Peiqing

doi:10.1016/j.abb.2014.08.007

Cited by 12 publications

(8 citation statements)

References 48 publications

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“…Although cardiac hypertrophy initially might be compensatory and adaptive, prolonged pathological hypertrophy is deleterious and can lead to decompensation, diastolic dysfunction and ultimately heart failure and sudden death 4 . Thus, cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide 5 6 7 8 . Accumulating evidence suggests that the pathological hypertrophy response is coordinated by an orchestrated hypertrophic network that comprises numerous signalling pathways, including β-adrenergic receptor-cAMP-PKA, GPCR-Gaq/PLC-PKCα, phosphatidylinositol 3-kinase (PI3K)/AKT, Ca 2+ /calmodulin-dependent kinase II and small G protein-mitogen-activated protein kinase (MAPK) signalling cascades 1 9 10 .…”

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confidence: 99%

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Deng¹,

Wang²,

Ji³

et al. 2016

Nat Commun

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Although pathological cardiac hypertrophy represents a leading cause of morbidity and mortality worldwide, our understanding of the molecular mechanisms underlying this disease is still poor. Here, we demonstrate that suppressor of IKKɛ (SIKE), a negative regulator of the interferon pathway, attenuates pathological cardiac hypertrophy in rodents and non-human primates in a TANK-binding kinase 1 (TBK1)/AKT-dependent manner. Sike-deficient mice develop cardiac hypertrophy and heart failure, whereas Sike-overexpressing transgenic (Sike-TG) mice are protected from hypertrophic stimuli. Mechanistically, SIKE directly interacts with TBK1 to inhibit the TBK1-AKT signalling pathway, thereby achieving its anti-hypertrophic action. The suppression of cardiac remodelling by SIKE is further validated in rats and monkeys. Collectively, these findings identify SIKE as a negative regulator of cardiac remodelling in multiple animal species due to its inhibitory regulation of the TBK1/AKT axis, suggesting that SIKE may represent a therapeutic target for the treatment of cardiac hypertrophy and heart failure.

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confidence: 99%

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Deng¹,

Wang²,

Ji³

et al. 2016

Nat Commun

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“…Primary culture of neonatal rat cardiomyocytes As previously described [23] , NRCMs were isolated from the ventricles of 1-to 3-day-old Sprague-Dawley (SD) rats. Briefly, the hearts were removed immediately after the rats were anesthetized, and the minced ventricles were dispersed at 37°C in 0.08% trypsin solution approximately 12-14 times for 5 min each time.…”

Section: Antibodies and Reagentsmentioning

confidence: 99%

“…Western blot analyses were performed as previously described [23] . Proteins of cultured cells or rat left ventricular tissues were harvested using RIPA lysis buffer (Beyotime, Nantong, Jiangsu, China) containing a protease inhibitor cocktail (Sigma-Aldrich, USA) on ice.…”

Section: Western Blotmentioning

confidence: 99%

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C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling

Wang

Cai

et al. 2017

Acta Pharmacol Sin

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Phosphodiesterase-9A (PDE9A) expression is upregulated during cardiac hypertrophy and heart failure. Accumulating evidence suggests that PDE9A might be a promising therapeutic target for heart diseases. The present study sought to investigate the effects and underlying mechanisms of C33(S), a novel selective PDE9A inhibitor, on cardiac hypertrophy in vitro and in vivo. Treatment of neonatal rat cardiomyocytes (NRCMs) with PE (100 μmol/L) or ISO (1 μmol/L) induced cardiac hypertrophy characterized by significantly increased cell surface areas and increased expression of fetal genes (ANF and BNP). Furthermore, PE or ISO significantly increased the expression of PDE9A in the cells; whereas knockdown of PDE9A significantly alleviated PE-induced hypertrophic responses. Moreover, pretreatment with PDE9A inhibitor C33(S) (50 and 500 nmol/L) or PF-7943 (2 μmol/L) also alleviated the cardiac hypertrophic responses in PE-treated NRCMs. Abdominal aortic constriction (AAC)-induced cardiac hypertrophy and ISO-induced heart failure were established in SD rats. In ISO-treated rats, oral administration of C33(S) (9, 3, and 1 mg·kg·d, for 3 consecutive weeks) significantly increased fractional shortening (43.55%±3.98%, 54.79%±1.95%, 43.98%±7.96% vs 32.18%±6.28%), ejection fraction (72.97%±4.64%, 84.29%±1.56%, 73.41%±9.37% vs 49.17%±4.20%) and cardiac output (60.01±9.11, 69.40±11.63, 58.08±8.47 mL/min vs 48.97±2.11 mL/min) but decreased the left ventricular internal diameter, suggesting that the transition to heart failure was postponed by C33(S). We further revealed that C33(S) significantly elevated intracellular cGMP levels, phosphorylation of phospholamban (PLB) and expression of SERCA2a in PE-treated NRCMs in vitro and in ISO-induced heart failure model in vivo. Our results demonstrate that C33(S) effectively protects against cardiac hypertrophy and postpones the transition to heart failure, suggesting that it is a promising agent in the treatment of cardiac diseases.

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“…However, more recent examination of ING3 function in regulating cardiac hypertrophy indicated a positive growth effect through mTOR [23], and using new, more reliable immunological reagents than were previously available, we found that ING3 is highly expressed in proliferating human tissues such as skin, small intestine, and bone marrow [24]. …”

Section: Introductionmentioning

confidence: 99%

ING3 promotes prostate cancer growth by activating the androgen receptor

Nabbi

McClurg

Thalappilly

et al. 2017

BMC Med

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BackgroundThe androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development.MethodsBiopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3.ResultsWe find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more accurate prognosis in primary prostate cancer.ConclusionsIn contrast to the majority of previous reports suggesting tumor suppressive functions in other cancers, our observations identify a clear oncogenic role for ING3, which acts as a co-activator of AR in prostate cancer. Data from TCGA and our previous and current tissue microarrays suggest that ING3 levels correlate with AR levels and that in patients with low levels of the receptor, ING3 level could serve as a useful prognostic biomarker.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0854-0) contains supplementary material, which is available to authorized users.

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Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling

Cited by 12 publications

References 48 publications

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

Suppressor of IKKɛ is an essential negative regulator of pathological cardiac hypertrophy

C33(S), a novel PDE9A inhibitor, protects against rat cardiac hypertrophy through upregulating cGMP signaling

ING3 promotes prostate cancer growth by activating the androgen receptor

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