HDAC6 Signaling at Primary Cilia Promotes Proliferation and Restricts Differentiation of Glioma Cells

Histone deacetylase 6 (HDAC6) is an emerging therapeutic target that is overexpressed in glioblastoma when compared to other HDACs. HDAC6 catalyzes the deacetylation of alpha-tubulin and mediates the disassembly of primary cilia, a process required for cell cycle progression. HDAC6 inhibition disrupts glioma proliferation, but whether this effect is dependent on tumor cell primary cilia is unknown. We found that HDAC6 inhibitors ACY-1215 (1215) and ACY-738 (738) inhibited the proliferation of multiple patient-derived and mouse glioma cells. While both inhibitors triggered rapid increases in acetylated alpha-tubulin (aaTub) in the cytosol and led to increased frequencies of primary cilia, they unexpectedly reduced the levels of aaTub in the cilia. To test whether the antiproliferative effects of HDAC6 inhibitors are dependent on tumor cell cilia, we generated patient-derived glioma lines devoid of cilia through depletion of ciliogenesis genes ARL13B or KIF3A. At low concentrations, 1215 or 738 did not decrease the proliferation of cilia-depleted cells. Moreover, the differentiation of glioma cells that was induced by HDAC6 inhibition did not occur after the inhibition of cilia formation. These data suggest HDAC6 signaling at primary cilia promotes the proliferation of glioma cells by restricting their ability to differentiate. Surprisingly, overexpressing HDAC6 did not reduce cilia length or the frequency of ciliated glioma cells, suggesting other factors are required to control HDAC6-mediated cilia disassembly in glioma cells. Collectively, our findings suggest that HDAC6 promotes the proliferation of glioma cells through primary cilia.

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Cell cycle progression by the repression of primary cilia formation in proliferating cells

Cellular and Molecular Life Sciences ◽

10.1007/s00018-013-1302-8 ◽

2013 ◽

Vol 70 (20) ◽

pp. 3893-3905 ◽

Cited By ~ 78

Author(s):

Hidemasa Goto ◽

Akihito Inoko ◽

Masaki Inagaki

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Primary Cilia ◽

Proliferating Cells ◽

Cycle Progression ◽

Cilia Formation

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MiR-15b Targets Cyclin D1 to Regulate Proliferation and Apoptosis in Glioma Cells

BioMed Research International ◽

10.1155/2014/687826 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 29

Author(s):

Guan Sun ◽

Lei Shi ◽

Shushan Yan ◽

Zhengqiang Wan ◽

Nan Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Cyclin D1 ◽

Cell Cycle Progression ◽

Therapeutic Strategy ◽

Glioma Cells ◽

Luciferase Assay ◽

Luciferase Reporter ◽

Cycle Progression ◽

Cycle Arrest ◽

Proliferation And Apoptosis

Aim. To investigate the role and mechanism of miR-15b in the proliferation and apoptosis of glioma.Methods. The miR-15b mimics were transfected into human glioma cells to upregulate the miR-15b expression. Cyclin D1 was determined by both western blotting analysis and luciferase reporter assay. Methylthiazol tetrazolium (MTT) and flow cytometry were employed to detect the cell proliferation, cell cycle, and apoptosis.Results. Overexpression of miR-15b inhibits proliferation by arrested cell cycle progression and induces apoptosis, possibly by directly targeting Cyclin D1. Both luciferase assay and bioinformatics search revealed a putative target site of miR-15b binding to the 3′-UTR of Cyclin D1. Moreover, expression of miR-15b in glioma tissues was found to be inversely correlated with Cyclin D1 expression. Enforced Cyclin D1 could abrogate the miR-15b-mediated cell cycle arrest and apoptosis.Conclusions. Our findings identified that miR-15b may function as a glioma suppressor by targeting the Cyclin D1, which may provide a novel therapeutic strategy for treatment of glioma.

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Inhibition of NF-kB activation confers sensitivity to TNFa by impairment of cell-cycle progression in human glioma cells

European Journal of Cancer ◽

10.1016/s0959-8049(99)80797-7 ◽

1999 ◽

Vol 35 ◽

pp. S104 ◽

Cited By ~ 3

Author(s):

G. Otsuka ◽

T. Nagaya ◽

K. Saito ◽

M. Mizuno ◽

J. Yoshida ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Glioma Cells ◽

Human Glioma ◽

Human Glioma Cells ◽

Cycle Progression

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Two polyamine analogs (BE-4-4-4 and BE-4-4-4-4) directly affect growth, survival, and cell cycle progression in two human brain tumor cell lines

Cancer Chemotherapy and Pharmacology ◽

10.1007/bf00686190 ◽

1995 ◽

Vol 36 (5) ◽

pp. 411-417 ◽

Cited By ~ 6

Author(s):

Christophe J. Bergeron ◽

Hirak S. Basu ◽

Laurence J. Marton ◽

Dennis F. Deen ◽

Malgorzata Pellarin ◽

...

Keyword(s):

Cell Cycle ◽

Brain Tumor ◽

Tumor Cell ◽

Human Brain ◽

Cell Cycle Progression ◽

Tumor Cell Lines ◽

Human Brain Tumor ◽

Cycle Progression ◽

Brain Tumor Cell ◽

Polyamine Analogs

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Alpha-Tubulin Acetylation in Trypanosoma cruzi: A Dynamic Instability of Microtubules Is Required for Replication and Cell Cycle Progression

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.642271 ◽

2021 ◽

Vol 11 ◽

Author(s):

Victoria Lucia Alonso ◽

Mara Emilia Carloni ◽

Camila Silva Gonçalves ◽

Gonzalo Martinez Peralta ◽

Maria Eugenia Chesta ◽

...

Keyword(s):

Cell Cycle ◽

Trypanosoma Cruzi ◽

Basal Body ◽

Mitotic Spindle ◽

Cell Cycle Progression ◽

Dynamic Instability ◽

Cycle Progression ◽

Alpha Tubulin ◽

Over Expression ◽

Tubulin Acetylation

Trypanosomatids have a cytoskeleton arrangement that is simpler than what is found in most eukaryotic cells. However, it is precisely organized and constituted by stable microtubules. Such microtubules compose the mitotic spindle during mitosis, the basal body, the flagellar axoneme and the subpellicular microtubules, which are connected to each other and also to the plasma membrane forming a helical arrangement along the central axis of the parasite cell body. Subpellicular, mitotic and axonemal microtubules are extensively acetylated inTrypanosoma cruzi. Acetylation on lysine (K) 40 of α-tubulin is conserved from lower eukaryotes to mammals and is associated with microtubule stability. It is also known that K40 acetylation occurs significantly on flagella, centrioles, cilia, basal body and the mitotic spindle in eukaryotes. Several tubulin posttranslational modifications, including acetylation of K40, have been cataloged in trypanosomatids, but the functional importance of these modifications for microtubule dynamics and parasite biology remains largely undefined. The primary tubulin acetyltransferase was recently identified in several eukaryotes as Mec-17/ATAT, a Gcn5-related N-acetyltransferase. Here, we report thatT. cruziATAT acetylates α-tubulinin vivoand is capable of auto-acetylation.TcATAT is located in the cytoskeleton and flagella of epimastigotes and colocalizes with acetylated α-tubulin in these structures. We have expressedTcATAT with an HA tag using the inducible vector pTcINDEX-GW inT. cruzi. Over-expression ofTcATAT causes increased levels of the alpha tubulin acetylated species, induces morphological and ultrastructural defects, especially in the mitochondrion, and causes a halt in the cell cycle progression of epimastigotes, which is related to an impairment of the kinetoplast division. Finally, as a result ofTcATAT over-expression we observed that parasites became more resistant to microtubule depolymerizing drugs. These results support the idea that α-tubulin acetylation levels are finely regulated for the normal progression ofT. cruzicell cycle.

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KIF14 controls ciliogenesis via regulation of Aurora A and is important for Hedgehog signaling

The Journal of Cell Biology ◽

10.1083/jcb.201904107 ◽

2020 ◽

Vol 219 (6) ◽

Cited By ~ 6

Author(s):

Petra Pejskova ◽

Madeline Louise Reilly ◽

Lucia Bino ◽

Ondrej Bernatik ◽

Linda Dolanska ◽

...

Keyword(s):

Cell Cycle ◽

Primary Cilium ◽

Hedgehog Signaling ◽

Cell Cycle Progression ◽

Primary Cilia ◽

Aurora A ◽

Pathway Activation ◽

Cilia Formation ◽

Tightly Coupled ◽

Hh Signaling

Primary cilia play critical roles in development and disease. Their assembly and disassembly are tightly coupled to cell cycle progression. Here, we present data identifying KIF14 as a regulator of cilia formation and Hedgehog (HH) signaling. We show that RNAi depletion of KIF14 specifically leads to defects in ciliogenesis and basal body (BB) biogenesis, as its absence hampers the efficiency of primary cilium formation and the dynamics of primary cilium elongation, and disrupts the localization of the distal appendage proteins SCLT1 and FBF1 and components of the IFT-B complex. We identify deregulated Aurora A activity as a mechanism contributing to the primary cilium and BB formation defects seen after KIF14 depletion. In addition, we show that primary cilia in KIF14-depleted cells are defective in response to HH pathway activation, independently of the effects of Aurora A. In sum, our data point to KIF14 as a critical node connecting cell cycle machinery, effective ciliogenesis, and HH signaling.

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Nek5 promotes centrosome integrity in interphase and loss of centrosome cohesion in mitosis

The Journal of Cell Biology ◽

10.1083/jcb.201412099 ◽

2015 ◽

Vol 209 (3) ◽

pp. 339-348 ◽

Cited By ~ 24

Author(s):

Suzanna L. Prosser ◽

Navdeep K. Sahota ◽

Laurence Pelletier ◽

Ciaran G. Morrison ◽

Andrew M. Fry

Keyword(s):

Cell Cycle ◽

Chromosome Segregation ◽

Cell Cycle Progression ◽

Primary Cilia ◽

Microtubule Nucleation ◽

Cycle Progression ◽

Spindle Formation ◽

Mitotic Entry ◽

Bipolar Spindle ◽

Centrosome Separation

Nek5 is a poorly characterized member of the NIMA-related kinase family, other members of which play roles in cell cycle progression and primary cilia function. Here, we show that Nek5, similar to Nek2, localizes to the proximal ends of centrioles. Depletion of Nek5 or overexpression of kinase-inactive Nek5 caused unscheduled separation of centrosomes in interphase, a phenotype also observed upon overexpression of active Nek2. However, separated centrosomes that resulted from Nek5 depletion remained relatively close together, exhibited excess recruitment of the centrosome linker protein rootletin, and had reduced levels of Nek2. In addition, Nek5 depletion led to loss of PCM components, including γ-tubulin, pericentrin, and Cdk5Rap2, with centrosomes exhibiting reduced microtubule nucleation. Upon mitotic entry, Nek5-depleted cells inappropriately retained centrosome linker components and exhibited delayed centrosome separation and defective chromosome segregation. Hence, Nek5 is required for the loss of centrosome linker proteins and enhanced microtubule nucleation that lead to timely centrosome separation and bipolar spindle formation in mitosis.

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Ruthenium(II) complex containing cinnamic acid derivative inhibits cell cycle progression at G0/G1 and induces apoptosis in melanoma cells

New Journal of Chemistry ◽

10.1039/d1nj04291b ◽

2022 ◽

Author(s):

Amanda Negreti ◽

Guilherme Álvaro Ferreira da Silva ◽

Carolina G Pressete ◽

Rafael Fonseca ◽

Caio Cesar Candido ◽

...

Keyword(s):

Cell Cycle ◽

Targeted Therapy ◽

Skin Cancer ◽

Tumor Cell ◽

Cell Cycle Progression ◽

Tumor Cell Lines ◽

Cinnamic Acid Derivative ◽

Cycle Progression ◽

Apoptotic Effect ◽

Malignant Tumor Cell

Melanoma is a highly aggressive skin cancer with limited targeted therapy arsenal. The Ruthenium-based complexes have shown interesting pro-apoptotic effect on malignant tumor cell lines. In this study three Ruthenium(II)...

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