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• Research Paper Volume 13, Issue 14 pp 18223-18237

  Combination of rapamycin and SAHA enhanced radiosensitization by inducing autophagy and acetylation in NSCLC

  Relevance score: 11.91458

  Yong Wang, Fen Liu, Chen Fang, Liyao Xu, Lin Chen, Zeyao Xu, Jiaquan Chen, Wei Peng, Biqi Fu, Yong Li

  Keywords: autophagy, DNA damage, histone deacetylase inhibitor, radiation, rapamycin

  Published in Aging on July 28, 2021

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  Radiotherapy plays an essential role in the treatment of non-small-cell lung cancer (NSCLC). However, cancer cells' resistance to ionizing radiation (IR) is the primary reason for radiotherapy failure leading to tumor relapse and metastasis. DNA double-strand breaks (DSB) repair after IR is the primary mechanism of radiotherapy resistance. In this study, we investigated the effects of autophagy-inducing agent, Rapamycin (RAPA), combined with the histone deacetylase inhibitor (HDACi), Suberoylanilide Hydroxamic Acid (SAHA), on the radiosensitivity of A549 and SK-MES-1 cells, and examined the combination effects on DNA damage repair, and determined the level of autophagy and acetylation in A549 cells. We also investigated the combination treatment effect on the growth of A549 xenografts after radiotherapy, and the level of DNA damage, autophagy, and acetylation. Our results showed that RAPA combined with SAHA significantly increased the inhibitory effect of radiotherapy compared with the single treatment group. The combined treatment increased the expression of DNA damage protein γ-H2AX and decreased DNA damage repair protein expression. RAPA combined with SAHA was induced mainly by regulating acetylation levels and autophagy. The effect of combined treatment to increase radiotherapy sensitivity will be weakened by inhibiting the level of autophagy. Besides, the combined treatment also showed a significantly inhibited tumor growth in the A549 xenograft model. In conclusion, these results identify a potential therapeutic strategy of RAPA combined with SAHA as a radiosensitizer to decreased DSB repair and enhanced DNA damage by inducing acetylation levels and autophagy for NSCLC.

• Research Paper Volume 13, Issue 11 pp 15336-15352

  Pharmacological targeting of TNS3 with histone deacetylase inhibitor as a therapeutic strategy in esophageal squamous cell carcinoma

  Relevance score: 9.629709

  Yang Shi, Zheng Xiang, Huiyu Yang, Suliman Khan, Ruizhe Li, Siran Zhou, Saif Ullah, Jiyu Zhang, Bingrong Liu

  Keywords: histone acetylation, histone deacetylase inhibitors, LMK-235, esophageal squamous cell carcinoma, tensin-3

  Published in Aging on May 28, 2021

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  Histone acetylation which regulates about 2-10% of genes has been demonstrated to be involved in tumorigenesis of esophageal squamous cell carcinoma (ESCC). In this study, we investigated the treatment response of ESCC to selective histone deacetylase inhibitor (HDACi) LMK-235 and potential biomarker predicting the treatment sensitivity. We identified tensin-3 (TNS3) which was highly over-expressed in ESCC as one of the down-regulated genes in response to LMK-235 treatment. TNS3 was found positively correlated with the tumor malignancy and poor prognosis in the patients. Silencing TNS3 significantly inhibited ESCC cell proliferation both in vitro and in vivo, sensitizing the treatment response to LMK-235. Our findings provide an insight into understanding the oncogenic role of TNS3 in ESCC and its clinical application for HDAC targeted therapy of ESCC.

• Research Paper Volume 13, Issue 7 pp 9820-9837

  Inhibition of HDAC6 by Tubastatin A reduces chondrocyte oxidative stress in chondrocytes and ameliorates mouse osteoarthritis by activating autophagy

  Relevance score: 13.369336

  Zhonghai Shen, Kang Ji, Zhenhai Cai, Chenglong Huang, Xiaojun He, Hongwei Xu, Gang Chen

  Keywords: histone deacetylase, Tubastatin A, osteoarthritis, autophagy

  Published in Aging on March 19, 2021

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  The aim of this study was to determine the effect of HDAC6 inhibition using the selective inhibitor Tubastatin A (TubA) on the regulation of tert-butyl hydroperoxide (TBHP)-treated chondrocytes and a mouse OA model. Using conventional molecular biology methods, our results showed that the level of HDAC6 increases both in the cartilage of osteoarthritis (OA) mice and TBHP-treated chondrocytes in vitro. TubA treatment effectively inhibits the expression of HDAC6, attenuates oxidative stress, reduces the level of apoptotic proteins to maintain chondrocyte survival, and suppresses the extracellular matrix (ECM) degradation. In addition, our results also revealed that HDAC6 inhibition by TubA activates autophagy in chondrocytes, whereas the protective effects of TubA were abolished by autophagy inhibitor intervention. Subsequently, the positive effects of HDAC6 inhibition by TubA were also found in a mouse OA model. Therefore, our study provide evidence that HDAC6 inhibition prevents OA development, and HDAC6 could be applied as a potential therapeutic target for OA management.

• Research Paper Volume 12, Issue 24 pp 25581-25598

  A dual inhibitor targeting HMG-CoA reductase and histone deacetylase mitigates neurite degeneration in LRRK2-G2019S parkinsonism

  Relevance score: 9.043924

  Chin-Hsien Lin, Han-Yi Lin, Jim-Min Fang, Ching-Chow Chen

  Keywords: Parkinson’s disease, HMG-CoA reductase, histone deacetylase, leucine-rich repeat kinase, tubulin

  Published in Aging on November 24, 2020

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  Parkinson’s disease (PD) is among the most common neurodegenerative disorders, and its etiology involves both genetic and environmental factors. The leucine-rich repeat kinase (LRRK2) G2019S mutation is the most common genetic cause of familial and sporadic PD. Current treatment is limited to dopaminergic supplementation, as no disease-modifying therapy is available yet. Recent evidence reveals that HMG-CoA reductase (HMGR) inhibitors (statins) exert neuroprotection through anti-neuroinflammatory effects, and histone deacetylase (HDAC) inhibitors mitigate neurodegeneration by promoting the transcription of neuronal survival factors. We designed and synthesized a dual inhibitor, statin hydroxamate JMF3086, that simultaneously inhibits HMGR and HDAC, and examined its neuroprotective effects on LRRK2-G2019S parkinsonism. JMF3086 restored dopaminergic neuron loss in aged LRRK2-G2019S flies and rescued neurite degeneration in primary hippocampal and dopaminergic neurons isolated from transgenic LRRK2-G2019S mice. The molecular mechanisms included downregulation of ERK1/2 phosphorylation, increased anti-apoptotic Akt phosphorylation, and inhibition of GSK3β activity to maintain cytoskeletal stability in stably transfected LRRK2-G2019S SH-SY5Y human dopaminergic cells. JMF3086 also promoted a-tubulin acetylation and kinesin-1 expression, facilitating antegrade mitochondrial transport in axons. Our findings demonstrate that JMF3086 exerted beneficial effects on restoring LRRK2-G2019S neurite degeneration by maintaining microtubule stability. This dual-target compound may be a promising mechanism-based therapy for PD.

• Research Paper Volume 12, Issue 16 pp 16083-16098

  Chidamide, a histone deacetylase inhibitor, inhibits autophagy and exhibits therapeutic implication in chronic lymphocytic leukemia

  Relevance score: 12.820817

  Yi-Lin Kong, Bi-Hui Pan, Jin-Hua Liang, Hua-Yuan Zhu, Li Wang, Yi Xia, Jia-Zhu Wu, Lei Fan, Jian-Yong Li, Wei Xu

  Keywords: chronic lymphocytic leukemia, autophagy, chidamide, histone deacetylase inhibitor

  Published in Aging on August 27, 2020

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  Novel agents have made the management of chronic lymphocytic leukemia (CLL) more promising and personalized. However, long-term treatment is still warranted which may result in toxicity and resistance. Thus, new combination therapy may help achieve deeper remission and limited-duration therapy. Histone deacetylase inhibitors (HDACi) can affect many tumors by modulating key biological functions including autophagy. Studies have shown that some novel targeted agents including ibrutinib induce autophagy. This study aimed to explore the effect of oral HDAC inhibitor, chidamide, on CLL cells as well as the role of autophagy in this process. Here, we showed that autophagy flux in CLL cells was inhibited by chidamide via post-transcriptional modulation and chidamide had cytostatic and cytotoxic effects on CLL cells. Besides, the pro-survival role of autophagy in CLL cells was validated by using autophagy inhibitor and knocking down critical autophagy gene. Notably, a combination of chidamide and ibrutinib showed significant synergism and downregulated ibrutinib-induced autophagy. This work highlights the therapeutic potential of chidamide via its effect on autophagy, especially in combination with ibrutinib.

• Research Paper Volume 12, Issue 17 pp 16759-16774

  HDAC4 inhibition disrupts TET2 function in high-risk MDS and AML

  Relevance score: 11.637801

  Feiteng Huang, Jie Sun, Wei Chen, Xin He, Yinghui Zhu, Haojie Dong, Hanying Wang, Zheng Li, Lei Zhang, Samer Khaled, Guido Marcucci, Jinwen Huang, Ling Li

  Keywords: myelodysplastic syndromes, acute myeloid leukemia, histone deacetylase, TET2

  Published in Aging on July 29, 2020

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  Aberrant DNA methylation often silences transcription of tumor-suppressor genes and is considered a hallmark of myeloid neoplasms. Similarly, histone deacetylation represses transcription of genes responsible for cell differentiation/death. A previous clinical study suggested potential pharmacodynamic antagonism between histone deacetylase inhibitors (HDACi) and DNA hypomethylating agents (HMA). Herein, to determine such antagonism, we used MDS/AML lines and NHD13 transgenic mice, and demonstrated that treatment with the pan-HDACi suberoylanilide hydroxamic acid (SAHA) significantly decreased TET2 expression and global 5-hydroxymethylcytosine (5hmC) levels. Mechanistically, our RNAi screen revealed that HDAC4 was responsible for maintaining TET2 levels. Accordingly, HDAC4 knockout reduced expression levels of MTSS1, a known TET2 target, an event associated with decreased 5hmC enrichment on the MTSS1 enhancer. Retrospective analysis of GEO datasets demonstrated that lower HDAC4 levels predict worse prognosis for AML patients. In an MDS-L xenografted immunodeficient mouse model, vitamin C co-treatment prevented TET2 loss of activity seen following SAHA treatment. Accordingly, vitamin C co-treatment further reduced MDS-L cell engraftment relative to SAHA alone. In summary, our findings suggest that co-administration of a TET2 agonist with pan-HDACi treatment could effectively counter potential diminution in TET2 activity resulting from pan-HDACi treatment alone, providing a rationale for evaluating such combinations against high-risk MDS/AML.

• Research Paper Volume 8, Issue 6 pp 1236-1248

  Overexpressed HDAC4 is associated with poor survival and promotes tumor progression in esophageal carcinoma

  Relevance score: 10.89262

  Li-Si Zeng, Xian-Zi Yang, Yue-Feng Wen, Shi-Juan Mai, Meng-He Wang, Mei-Yin Zhang, X.F. Steven Zheng, Hui-Yun Wang

  Keywords: histone deacetylase 4, esophageal carcinoma, cell proliferation, cell cycle, epithelial-mesenchymal transition

  Published in Aging on June 13, 2016

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  Histone deacetylases (HDACs) mediate histone deacetylation, leading to transcriptional repression, which is involved in many diseases, including age-related tissue degeneration, heart failure and cancer. In this study, we were aimed to investigate the expression, clinical significance and biological function of HDAC4 in esophageal carcinoma (EC). We found that HDAC4 mRNA and protein are overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. HDAC4 overexpression is associated with higher tumor grade, advanced clinical stage and poor survival. Mechanistically, HDAC4 promotes proliferation and G1/S cell cycle progression in EC cells by inhibiting cyclin-dependent kinase (CDK) inhibitors p21 and p27 and up-regulating CDK2/4 and CDK-dependent Rb phosphorylation. HDAC4 also enhances ESCC cell migration. Furthermore, HDAC4 positively regulates epithelial-mesenchymal transition (EMT) by increasing the expression of Vimentin and decreasing the expression of E-Cadherin/α-Catenin. Together, our study shows that HDAC4 overexpression is important for the oncogenesis of EC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy.

  

  (A) Real-time qRT-PCR analysis shows that expression of HDAC4 mRNA is significantly increased in 86 ESCC tissues compared with the corresponding normal tissues. **** P <0.001; (B) The expression of HDAC4 mRNA is significantly increased in EC cell lines, EC/CUHK1, KYSE30, KYSE140, KYSE150 and KYSE180 cell lines, compared with the human normal esophageal cell line NE1. The expression was normalized by GAPDH mRNA. * P <0.05; (C) Western blot analysis of HDAC4 protein expression in eight ESCC tissues and paired normal tissues; GAPDH was used as a loading control. (D) HDAC4 protein expression in eight ESCC tissues and paired adjacent tissues was quantitated using ImageJ software (Wayne Rashband). (E) Kaplan–Meier analysis shows that HDAC4 overexpression is significantly associated with poor overall survival in 86 ESCC cases (P <0.001, log-rank test). (F) Kaplan–Meier analysis shows that expression of HDAC4 is marginally significantly associated with poor relapse-free survival in 86 ESCC cases (P =0.056, log-rank test).

  
  
  

  

  Real-time qRT-PCR analysis of HDAC4 mRNA expression in (A) KYSE30 and (B) EC/CUHK1 cell lines transfected with HDAC4 specific siRNAs or a control siRNA. CCK8 assay was then performed to evaluate cell growth of (C) KYSE30 and (D) EC/CUHK1 cells). Each value represents the mean ± http://S.D.in three independent experiments. * P<0.05; ** P< 0.01. OD, optical density.

  
  
  

  

  (A and C) Flow cytometry analysis of indicated EC cells transfected with HDAC4-specific siRNAs or a control siRNA; G1-phase cells are significantly increased while S-phase cells are reduced in HDAC4 knockdown (B) KYSE30 and (D) EC/CUHK1 cells, * P <0.05; (E) HDAC4 down-regulation increases the expression of p21 and p27 proteins while reduces pRb, CDK2 and CDK4 in EC cells.

  
  
  

  

  (A) Knockdown of HDAC4 reduces migration of KYSE30 and EC/CUHK1 cells. EC cells were transiently transfected with HDAC4 siRNA or a control siRNA. The number of migrated cells is decreased in cells (x100 magnification) transfected with HDAC4 siRNAs compared with those transfected with a control siRNA. Wound healing assay demonstrates that down-regulation of HDAC4 inhibits cell migration at 12 h and 24 h in (B) KYSE30 and (C) EC/CUHK1 cells (magnification, x100). (D) Western blot analysis indicates that knockdown of HDAC4 increases the expression of E-cadherin and α-catenin, and decreases the expression of Vimentin.

  
  
  

• Research Paper Volume 2, Issue 10 pp 659-668

  Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes

  Relevance score: 10.178203

  Tom C Karagiannis, Ann JE Lin, Katherine Ververis, Lisa Chang, Michelle M Tang, Jun Okabe, Assam El-Osta

  Keywords: Cardiac hypertrophy, doxorubicin, cardiomyocyte, cardiac differentiation, histone deacetylase inhibitor, Trichostatin A

  Published in Aging on September 17, 2010

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  Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer.

  

  Retinoic acid induces differentiation of embryonic H9c2 myoblasts to cardiomyocytes in low serum supplemented with retinoic acid. Rat embryonic heart-derived myoblasts maintained in DMEM containing 10% FBS (A) were cultured in DMEM containing 1% FBS for seven days resulting in differentiation to skeletal muscle (B). A seven day culture in low serum media supplemented with 10 nM retinoic acid resulted in differentiation into cardiac myocytes (C). RT-PCR quantitation of MLC-2v transcripts (which display absolute cardiac tissue specificity) indicates overexpression of the gene in retinoic acid treated cells compared to cells cultured in low serum without retinoic acid (mean ± standard deviations of triplicates from a representative experiment, total of three independent experiments, (D). Bar = 5 μm; x 20 magnification.

  
  
  

  

  Doxorubicin (Dox) induces a dose-dependent hypertrophic response in rat H9c2 cardiomyocytes. Cells were treated with the indicated concentrations of doxorubicin for two hrs and cultured in fresh media for a further 24 hours prior to quantitation of cell volume (A) and total protein content per cell (B). Phase-contrast images of control untreated H9c2 myocytes (C) compared to cells treated with 1 μM doxorubicin (2 hr treatment followed by 24 hour incubation in fresh media, D). Bar = 5 μm; x 20 magnification.

  
  
  

  

  Doxorubicin modulates the expression of cardiac hypertrophy-associated genes in H9c2 myocytes. QT-PCR analysis of MLC-2v, α-MHC and ANP transcripts in cells treated with the indicated concentrations of doxorubicin for 2 hours followed by a 24 hour treatment in fresh media. Fold change of mRNA expression shown relative to untreated control H9c2 cells; mean ± standard deviations of triplicates from a representative experiment (total of three independent experiments) are indicated.

  
  
  

  

  Trichostatin A (TSA) potentiates doxorubicin-induced hypertrophic responses in H9c2 cardiomyocytes by modulating the expression of hypertrophy-associated genes. QT-PCR analysis of MLC-2v, α-MHC and ANP transcripts in cells treated with 1 μM doxorubicin (Dox) for 2 hours followed by a 24 hour treatment in fresh media in the presence and absence of 1 μM TSA. Fold change of mRNA expression shown relative to untreated control H9c2 cells; mean ± standard deviations of triplicates from a representative experiment (total of three independent experiments) are indicated.

  
  
  

  

  Trichostatin A (TSA) augments doxorubicin-induced accumulation of γH2AX foci in H9c2 cardiomyoctes. Cells pretreated with the indicated concentration of TSA for 24 hours were exposed to 1 μM doxorubicin for 1 hour, followed by a 24 hour treatment in fresh media. Cells were then stained for γH2AX foci, images were acquired with a Zeiss LSM 510 Meta Confocal microscope using 0.5 μm Z-sectioning and foci were quantitated using Metamorph (A). Mean ± standard deviations from two independent experiments (total of five independent experiments) are indicated (*p<0.001). Immunofluorescence visualization of γH2AX foci (B) in untreated H9c2 cells (i), cells treated with 1 μM TSA (ii), cells treated with 1 μM doxorubicin (iii) and cells treated with a combination of TSA and doxorubicin (iv) as described above. Bar = 2 μm; x 63 magnification.

  
  
  

• Research Paper pp undefined-undefined

  Histone deacetylase 4 reverses cellular senescence via DDIT4 in dermal fibroblasts

  Relevance score: 9.977033

  Yuri Lee, Min Ji Song, Ji Hwan Park, Mi Hee Shin, Min-Kyoung Kim, Daehee Hwang, Dong Hun Lee, Jin Ho Chung

  Keywords: cellular senescence, DNA damage-inducible transcript 4, histone deacetylase 4, oxidative stress, ultraviolet light

  Published in Aging on Invalid Date

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  Histone deacetylases (HDACs) remove acetyl groups from lysine chains on histones and other proteins and play a crucial role in epigenetic regulation and aging. Previously, we demonstrated that HDAC4 is consistently downregulated in aged and ultraviolet (UV)-irradiated human skin in vivo. Cellular senescence is a permanent cell cycle arrest induced by various stressors. To elucidate the potential role of HDAC4 in the regulation of cellular senescence and skin aging, we established oxidative stress- and UV-induced cellular senescence models using primary human dermal fibroblasts (HDFs). RNA sequencing after overexpression or knockdown of HDAC4 in primary HDFs identified candidate molecular targets of HDAC4. Integrative analyses of our current and public mRNA expression profiles identified DNA damage-inducible transcript 4 (DDIT4) as a critical senescence-associated factor regulated by HDAC4. Indeed, DDIT4 and HDAC4 expressions were downregulated during oxidative stress- and UV-induced senescence. HDAC4 overexpression rescued the senescence-induced decrease in DDIT4 and senescence phenotype, which were prevented by DDIT4 knockdown. In addition, DDIT4 overexpression reversed changes in senescence-associated secretory phenotypes and aging-related genes, suggesting that DDIT4 mediates the reversal of cellular senescence via HDAC4. Collectively, our results identify DDIT4 as a promising target regulated by HDAC4 associated with cellular senescence and epigenetic skin aging.