The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis

Lee, Yi-Shan; Lim, Kian-Huat; Guo, Xing Rong; Kawaguchi, Yoshiharu; Gao, Ya-sheng; Barrientos, Tomasa; Ordentlich, Peter; Wang, Xiaofan; Counter, Christopher M.; Yao, Tso‐Pang

doi:10.1158/0008-5472.can-08-0188

Cited by 240 publications

(246 citation statements)

References 56 publications

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“…Our findings are consistent with this report and add GRP78 to the list of molecular chaperones that are acetylated following inhibition of HDAC6, i.e., HDAC6 "acetylome", which includes a growing list of proteins (36). In transformed cells, activation of the RAS-RAF-MEK-ERK pathway and a basal state of proteotoxic stress induces GRP78 and HDAC6 levels (33,(37)(38)(39). Increased levels of GRP78 also result from an adaptive response to proteotoxic stress and UPR and confer resistance to apoptosis (2,(4)(5)(6)(7)20).…”

Section: Discussionsupporting

confidence: 92%

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Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Rao

Nalluri

Kolhe

et al. 2010

Molecular Cancer Therapeutics

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Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1α, which results in the adaptive unfolded protein response (UPR). In the present studies, we determined that histone deacetylase-6 (HDAC6) binds and deacetylates GRP78. Following treatment with the pan-histone deacetylase inhibitor panobinostat (Novartis Pharmaceuticals), or knockdown of HDAC6 by short hairpin RNA, GRP78 is acetylated in 11 lysine residues, which dissociates GRP78 from PERK. This is associated with the activation of a lethal UPR in human breast cancer cells. Coimmunoprecipitation studies showed that binding of HDAC6 to GRP78 requires the second catalytic and COOH-terminal BUZ domains of HDAC6. Treatment with panobinostat increased the levels of phosphorylated-eukaryotic translation initiation factor (p-eIF2α), ATF4, and CAAT/enhancer binding protein homologous protein (CHOP). Panobinostat treatment also increased the proapoptotic BIK, BIM, BAX, and BAK levels, as well as increased the activity of caspase-7. Knockdown of GRP78 sensitized MCF-7 cells to bortezomib and panobinostat-induced UPR and cell death. These findings indicate that enforced acetylation and decreased binding of GRP78 to PERK is mechanistically linked to panobinostat-induced UPR and cell death of breast cancer cells. Mol Cancer Ther; 9(4); 942-52. ©2010 AACR.

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Section: Discussionsupporting

confidence: 92%

“…1C; refs. [32][33][34]. Taken together, these findings indicate that HDAC6 is also a deacetylase for GRP78.…”

Section: Inhibition Of Hdac6 Activity Induces Acetylation Of Grp78mentioning

confidence: 59%

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Rao

Nalluri

Kolhe

et al. 2010

Molecular Cancer Therapeutics

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“…In addition, it is conceivable that HDAC6 mainly functions in pathologic settings in mammals (e.g., during vascular injury or malignancy). Recent studies have demonstrated that HDAC6-deficient mice are resistant to carcinogen-induced skin tumors, suggesting a critical role for this deacetylase in cancer development (Lee et al, 2008). Therefore, it would be of great importance to investigate in the future the potential role of HDAC6 in tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

Xie

Ren

et al. 2011

Protein Cell

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Angiogenesis, a process by which the preexisting blood vasculature gives rise to new capillary vessels, is associated with a variety of physiologic and pathologic conditions. However, the molecular mechanism underlying this important process remains poorly understood. Here we show that histone deacetylase 6 (HDAC6), a microtubule-associated enzyme critical for cell motility, contributes to angiogenesis by regulating the polarization and migration of vascular endothelial cells. Inhibition of HDAC6 activity impairs the formation of new blood vessels in chick embryos and in angioreactors implanted in mice. The requirement for HDAC6 in angiogenesis is corroborated in vitro by analysis of endothelial tube formation and capillary sprouting. Our data further show that HDAC6 stimulates membrane ruffling at the leading edge to promote cell polarization. In addition, microtubule end binding protein 1 (EB1) is important for HDAC6 to exert its activity towards the migration of endothelial cells and generation of capillary-like structures. These results thus identify HDAC6 as a novel player in the angiogenic process and offer novel insights into the molecular mechanism governing endothelial cell migration and angiogenesis.

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“…There is considerable evidence suggesting that HER-2 overexpression induces neoplastic cell transformation and oncogenic tumorigenesis (43)(44)(45). In addition, TPA and EGF are associated with a neoplastic cell transformation in JB6 Cl41 cells (46)(47)(48).…”

Section: Discussionmentioning

confidence: 99%

The Prolyl Isomerase Pin1 Enhances HER-2 Expression and Cellular Transformation via Its Interaction with Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase 1

Khanal

Namgoong

Kang

et al. 2010

Molecular Cancer Therapeutics

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The HER-2 oncogene, a member of the erythroblastosis oncogene B (ERBB)-like oncogene family, has been shown to be amplified in many types of cancer, including breast cancer. However, the molecular mechanism of HER-2 overexpression is not completely understood. The phosphorylation of proteins on the serine or threonine residues that immediately precede proline (pSer/Thr-Pro) is specifically catalyzed by the prolyl isomerase Pin1 and is a key signaling mechanism in cell proliferation and transformation. Here, we found that Pin1 interacts with mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) protein kinase 1, resulting in the induction of HER-2 expression. Pin1 −/− mouse embryonic fibroblasts exhibited a decrease in epidermal growth factor (EGF)-induced MEK1/2 phosphorylation compared with Pin1 +/+ mouse embryonic fibroblast. In addition, a knockdown of Pin1 resulted in the inhibition of MEK1/2 phosphorylation induced by EGF in MCF-7 cells. Furthermore, PD98059, a specific inhibitor of MEK1/2, and Juglone, a potent Pin1 inhibitor, markedly suppressed the expression of activator protein-2α and the HER-2 promoter activity induced by EGF or 12-O-tetradecanoylphorbol-13-acetate in MCF-7 cells. Importantly, these inhibitors inhibited the neoplastic cell transformation induced by EGF in Pin1-overexpressing JB6 Cl41 cells, which showed enhanced cellular formation compared with the control cells. Therefore, Juglone and PD98059 inhibited the colony formation of MCF-7 breast cancer cells in soft agar. These results indicate that Pin1 amplifies EGF signaling in breast cancer cells through its interaction with MEK1 and then enhances HER-2 expression, suggesting that Pin1 plays an important role in the overexpression of HER-2 through Pin1-MEK1-activator protein-2α signaling in breast cancer. Mol Cancer Ther; 9(3); 606-16. ©2010 AACR.

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The Cytoplasmic Deacetylase HDAC6 Is Required for Efficient Oncogenic Tumorigenesis

Cited by 240 publications

References 56 publications

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Treatment with Panobinostat Induces Glucose-Regulated Protein 78 Acetylation and Endoplasmic Reticulum Stress in Breast Cancer Cells

Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner

The Prolyl Isomerase Pin1 Enhances HER-2 Expression and Cellular Transformation via Its Interaction with Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase 1

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