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Hdac6 erk

Nicholas Forsythe, Alaa Refaat, Arman Javadi, Hajrah Khawaja, Jessica-Anne Weir, Heba Emam, Wendy L Allen, Frank Burkamp, Vlad Popovici, Puthen V Jithesh, Claudio Isella, Melissa J LaBonte, Ian G Mills, Patrick G Johnston, Sandra Van Schaeybroeck
BRAFV600E mutations occur in 10% of colorectal cancer (CRC) cases, are associated with poor survival and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT CRC. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n=31; validation set: n=26) CRC and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome...
February 26, 2018: Molecular Cancer Therapeutics
Jae-Hyeok Lee, Hyuck-Kwon Kwon, Hyeon-Jun Shin, Gwang-Hyeon Nam, Jae-Ho Kim, Sangdun Choi
Surface modification of micro- and nanotopography was employed to alter the surface properties of scaffolds for controlling cell attachment, proliferation, and differentiation. This study reports a method for generating multinucleated colonies as evidenced by spherical colony formation through nanotopography-induced expression of reprogramming factors in human dermal fibroblasts. Colony formation was achieved by subjecting the cells to specific environments such as culturing with single-walled carbon nanotubes and poly-l-lysine (PLL-SWCNTs)...
March 14, 2018: ACS Applied Materials & Interfaces
Hyun-Wook Ryu, Dong-Hee Shin, Dong Hoon Lee, Hye-Rim Won, So Hee Kwon
HDAC6-selective inhibitors are novel epigenetic anticancer agents. However, their precise mechanisms of action are incompletely understood. We investigated the anticancer mechanisms of the novel potent and selective HDAC6 inhibitor A452 compared with current clinically tested HDAC6 inhibitor ACY-1215. We demonstrate that A452 effectively inhibits the cell growth and viability of various cancer cell types, irrespective of p53 status. A452 induced apoptosis as evidenced by activated caspase 3 and PARP, increased Bak and Bax, and decreased Bcl-xL...
November 2, 2017: Carcinogenesis
Shiyi Yu, Xiuxiu Cai, Chenxi Wu, Yan Liu, Jun Zhang, Xue Gong, Xin Wang, Xiaoli Wu, Tao Zhu, Lin Mo, Jun Gu, Zhenghong Yu, Jinfei Chen, Jean Paul Thiery, Renjie Chai, Liming Chen
Breast cancer is the leading cause of women death. Heat shock protein 90 (HSP90) and Histone deacetylase 6 (HDAC6) are promising anti-cancer drug targets. However, it's still unclear the applicability of anti-HSP90 and anti-HDAC6 strategies in precision treatment of breast cancer. In current study, we found that triple negative breast cancer (TNBC) cells, compared to T47D, an ERα+ breast cancer cell line, exhibited 7~40 times lower IC50 values, stronger cell cycle perturbation, increased cell apoptosis and stronger inhibition of cell migration upon 17-DMAG treatment, while T47D, compared to TNBC cells, expressed higher HDAC6 and showed stronger anti-cancer response upon treatment of Tubacin...
2017: International Journal of Biological Sciences
Ueihuei Peng, Zhihao Wang, Sa Pei, Yunchao Ou, Pengchao Hu, Wanhong Liu, Jiquan Song
BRAFV600E mutation is found in ~50% of melanoma patients and BRAFV600E kinase activity inhibitor, vemurafenib, has achieved a remarkable clinical response rate. However, most patients treated with vemurafenib eventually develop resistance. Overcoming primary and secondary resistance to selective BRAF inhibitors remains one of the most critically compelling challenges for these patients. HDAC6 has been shown to confer resistance to chemotherapy in several types of cancer. Few studies focused on the role of HDAC6 in vemurafenib resistance...
February 2017: Oncology Reports
Jeong Ah Lim, Yong-Sung Juhnn
Stress conditions are correlated with tumor growth, progression and metastasis. We hypothesized that stress signals might affect tumor progression via epigenetic control of gene expression and investigated the effects of stress signals on the expression levels of histone deacetylases (HDACs) and the underlying mechanisms of these effects in lung cancer cells. Treatment with isoproterenol (ISO), an analog of the stress signal epinephrine, increased the expression of HDAC6 protein and mRNA in H1299 lung cancer cells...
January 15, 2016: Experimental & Molecular Medicine
Gi Soo Youn, Keun Wook Lee, Soo Young Choi, Jinseu Park
Although histone deacetylase 6 (HDAC6) has been implicated in inflammatory diseases, direct involvement and its action mechanism of HDAC6 in the transcriptional regulation of pro-inflammatory genes have been unclear. In this study, we investigated the possible role of HDAC6 in the expression of pro-inflammatory mediators, indicator of macrophage activation, in RAW 264.7 cells and primary mouse macrophages. HDAC6 overexpression significantly enhanced expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, with concomitant reduction in acetylated α-tubulin...
August 2016: Free Radical Biology & Medicine
Zhifei Wang, Yan Leng, Junyu Wang, Hsiao-Mei Liao, Joel Bergman, Peter Leeds, Alan Kozikowski, De-Maw Chuang
Histone deacetylase (HDAC) 6 exists exclusively in cytoplasm and deacetylates cytoplasmic proteins such as α-tubulin. HDAC6 dysfunction is associated with several pathological conditions in the central nervous system. This study investigated the beneficial effects of tubastatin A (TubA), a novel specific HDAC6 inhibitor, in a rat model of transient middle cerebral artery occlusion (MCAO) and an in vitro model of excitotoxicity. Post-ischemic TubA treatment robustly improved functional outcomes, reduced brain infarction, and ameliorated neuronal cell death in MCAO rats...
January 21, 2016: Scientific Reports
Sui-Chih Tien, Hsiao-Hui Lee, Ya-Chi Yang, Miao-Hsia Lin, Yu-Ju Chen, Zee-Fen Chang
Regulation of Shp2, a tyrosine phosphatase, critically influences the development of various diseases. Its role in epithelial lumenogenesis is not clear. Here we show that oncogenic Shp2 dephosphorylates Tuba to decrease Cdc42 activation, leading to the abnormal multi-lumen formation of epithelial cells. HDAC6 suppression reverses oncogenic Shp2-induced multiple apical domains and spindle mis-orientation during division in cysts to acquire normal lumenogenesis. Intriguingly, Cdc42 activity is not restored in this rescued process...
2016: Nature Communications
Chun-Han Chen, Chia-Hwa Lee, Jing-Ping Liou, Che-Ming Teng, Shiow-Lin Pan
Upregulation of class I histone deacetylases (HDAC) correlates with poor prognosis in colorectal cancer (CRC) patients. Previous study revealed that (E)-N-hydroxy-3-(1-(4-methoxyphenylsulfonyl)-1,2,3,4-tetrahydroquinolin-6-yl)acrylamide (Compound 11) is a potent and selective class I HDAC inhibitor, exhibited significant anti-proliferative activity in various human cancer cell lines. In current study, we demonstrated that compound 11 exhibited significant anti-proliferative and cytotoxic activity in CRC cells...
November 3, 2015: Oncotarget
Kiran Kumar Nakka, Nidhi Chaudhary, Shruti Joshi, Jyotsna Bhat, Kulwant Singh, Subhrangsu Chatterjee, Renu Malhotra, Abhijit De, Manas Kumar Santra, F Jeffrey Dilworth, Samit Chattopadhyay
Pre-mRNA splicing is a complex regulatory nexus modulated by various trans-factors and their posttranslational modifications to create a dynamic transcriptome through alternative splicing. Signal-induced phosphorylation and dephosphorylation of trans-factors are known to regulate alternative splicing. However, the role of other posttranslational modifications, such as deacetylation/acetylation, methylation, and ubiquitination, that could modulate alternative splicing in either a signal-dependent or -independent manner remain enigmatic...
June 30, 2015: Proceedings of the National Academy of Sciences of the United States of America
Gi Soo Youn, Sung Mi Ju, Soo Young Choi, Jinseu Park
Human immunodeficiency virus (HIV)-1 transactivator of transcription (Tat) is a viral protein that induces extensive neuroinflammation by up-regulating proinflammatory mediators, including cytokines, chemokines, and adhesion molecules. Histone deacetylase 6 (HDAC6) has been implicated in the transcriptional regulation of inflammatory genes. In this study, we investigated the possible role of HDAC6 in HIV-1 Tat-induced up-regulation of proinflammatory mediators in astrocytes. HIV-1 Tat augmented HDAC6 expression, which was correlated with a reduction in acetylated α-tubulin in CRT-MG human astroglioma cells and primary mouse astrocytes...
June 1, 2015: Glia
Elena Shagisultanova, Anna V Gaponova, Rashid Gabbasov, Emmanuelle Nicolas, Erica A Golemis
Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases...
August 1, 2015: Gene
Joshua Haakenson, Jheng-Yu Wu, Shengyan Xiang, Kendra A Williams, Wenlong Bai, Xiaohong Zhang
Histone deacetylase 6 (HDAC6) is emerging as a novel therapeutic target in cancer treatment. HDAC6 plays an important role in cell migration, cell transformation, and DNA damage response. Our and others' studies have linked HDAC6's functions and HDAC6's regulation to the mitogen-activated protein kinase (MAPK) pathways. In particular, HDAC6's activity has been found to be regulated by EGF-EGFR-Ras-Raf-MEK-ERK signaling. Inversely, HDAC6 has been reported to modulate the functions of EGFR and Ras. In this review, we summarize the literature on HDAC6 and MAPK pathways, and emphasize the interaction between HDAC6 and the ERK-MAPK signaling cascade...
2015: Critical Reviews in Oncogenesis
Jaganathan Kowshik, Hemant Giri, Tanagala Kranthi Kiran Kishore, Rushendhiran Kesavan, Raju Naik Vankudavath, Geereddy Bhanuprakash Reddy, Madhulika Dixit, Siddavaram Nagini
BACKGROUND: Blocking vascular endothelial growth factor (VEGF) mediated tumor angiogenesis by phytochemicals has emerged as an attractive strategy for cancer prevention and therapy. METHODS: We investigated the anti-angiogenic effects of ellagic acid in a hamster model of oral oncogenesis by examining the transcript and protein expression of hypoxia-inducible factor-1alpha (HIF-1α), VEGF, VEGFR2, and the members of the PI3K/Akt and MAPK signaling cascades. Molecular docking studies and cell culture experiments with the endothelial cell line ECV304 were performed to delineate the mechanism by which ellagic acid regulates VEGF signaling...
2014: Anti-cancer Agents in Medicinal Chemistry
Lei Zhang, Yingjie Zhang, C James Chou, Elizabeth S Inks, Xuejian Wang, Xiaoguang Li, Jinning Hou, Wenfang Xu
In the present work, a series of small molecules were designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compounds was discovered. Moreover, the tested compounds have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results show that representative compounds can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60...
March 2014: ChemMedChem
Kendra A Williams, Mu Zhang, Shengyan Xiang, Chen Hu, Jheng-Yu Wu, Shengping Zhang, Meagan Ryan, Adrienne D Cox, Channing J Der, Bin Fang, John Koomen, Eric Haura, Gerold Bepler, Santo V Nicosia, Patrick Matthias, Chuangui Wang, Wenlong Bai, Xiaohong Zhang
Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as α-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells. Yet, no connection between HDAC6 and ERK has been discovered. Here, for the first time, we reveal that ERK binds to and phosphorylates HDAC6 to promote cell migration via deacetylation of α-tubulin...
November 15, 2013: Journal of Biological Chemistry
Mei-Jen Chuang, Sheng-Tang Wu, Shou-Hung Tang, Xiang-Me Lai, Hsiao-Chu Lai, Kai-Hsiang Hsu, Kuang-Hui Sun, Guang-Huan Sun, Sun-Yran Chang, Dah-Shyong Yu, Pei-Wen Hsiao, Shih-Ming Huang, Tai-Lung Cha
Histone deacetylase inhibitors (HDACIs) have potent anti-cancer activity in a variety of cancer models. Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application. This study aimed to determine if a potent HDACI, LBH589 (Panobinostat), had differential therapeutic responsiveness towards LNCaP and PC-3 prostate cancer (PCa) cells. The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment, while the latter was less sensitive and had late G2 arrest...
2013: PloS One
S-C Tien, Z-F Chang
Deregulation of Shp2, a non-receptor tyrosine phosphatase, causes hyperactivation of extracellular signal-regulated kinase (ERK), leading to growth abnormality. Here, we show that inhibition of RhoA-Dia is sufficient to upregulate ERK activation in epithelial cells. Oncogenic Shp2 expression attenuates RhoA-Dia signaling, by which microtubule (MT) is destabilized with reduced level of acetylation. Either MT stabilization, silencing of histone deacetylase 6 (HDAC6) or enforcing RhoA-Dia signal prevents oncogenic Shp2-induced ERK hyperactivation...
May 29, 2014: Oncogene
Dae Joong Kim, Luis A Martinez-Lemus, George E Davis
Vascular tube morphogenesis requires the establishment of endothelial cell (EC) apical-basal polarity in three-dimensional (3D) extracellular matrices. To date, there is little understanding of how EC polarity is controlled during these highly dynamic and rapid morphogenic events. We show that the microtubule tip complex proteins, end binding 1 (EB1), p150(Glued), and Clasp1, control human EC tube formation by (1) inducing microtubule assembly and asymmetric cytoskeletal polarization, whereby acetylated and detyrosinated tubulins distribute in a subapical membrane location and filamentous actin distributes basally; (2) increasing tubulin posttranslational modifications, including required acetylation events; and (3) regulating an EC lumen signaling cascade that involves membrane type 1 matrix metallopatrinase (MT1-MMP)-dependent proteolysis as well as Pak, Raf, and Erk kinases...
April 25, 2013: Blood
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