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- RASSF1A Suppresses Cell Migration through Inactivation of HDAC6 and Increase of Acetylated alpha-Tubulin
- Hae-Yun Jung, Jun Seok Jung, Young Mi Whang, Yeul Hong Kim
- Cancer Res Treat. 2013;45(2):134-144. Published online June 30, 2013
- DOI: https://doi.org/10.4143/crt.2013.45.2.134
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Abstract
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ePub - PURPOSE
The RAS association domain family protein 1 (RASSF1) has been implicated in a tumor-suppressive function through the induction of acetylated alpha-tubulin and modulation of cell migration. However, the mechanisms of how RASSF1A is associated with acetylation of alpha-tubulin for controlling cell migration have not yet been elucidated. In this study, we found that RASSF1A regulated cell migration through the regulation of histon deacetylase 6 (HDAC6), which functions as a tubulin deacetylase.
MATERIALS AND METHODS
The cell migration was assessed using wound-healing and transwell assays. The role of RASSF1A on cell migration was examined by immunofluorescence staining, HDAC activity assay and western blot analysis.
RESULTS
Cell migration was inhibited and cell morphology was changed in RASSF1A-transfected H1299 cells, compared with controls, whereas HDAC6 protein expression was not changed by RASSF1A transfection in these cells. However, RASSF1A inhibited deacetylating activity of HDAC6 protein and induced acetylated alpha-tubulin expression. Furthermore, acetylated alpha-tubulin and HDAC6 protein were co-localized in the cytoplasm in RASSF1A-transfected H1299 cells. Conversely, when the endogenous RASSF1A expression in HeLa cells was blocked with RASSF1A siRNA treatment, acetylated alpha-tubulin was co-localized with HDAC6 protein throughout the whole cells, including the nucleus, compared with scramble siRNA-treated HeLa cells. The restoration of RASSF1A by 5-Aza-dC treatment also induced acetylated alpha-tubulin through inhibition of HDAC6 activity that finally resulted in suppressing cell migration in H1299 cells. To further confirm the role of HDAC6 in RASSF1A-mediated cell migration, the HDAC6 expression in H1299 cells was suppressed by using HDAC6 siRNA, and cell motility was found to be decreased through enhanced acetylated alpha-tubulin.
CONCLUSION
The results of this study suggest that the inactivation of HDAC6 by RASSF1A regulates cell migration through increased acetylated alpha-tubulin protein. -
Citations
Citations to this article as recorded by
- Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition
Hui Luo, Jianhua Chen, Cao Li, Tian Wu, Siyue Yin, Guangping Yang, Yipin Wang, Zhihan Guo, Saifei Hu, Yanni He, Yingnan Wang, Yao Chen, Youqiang Su, Congxiu Miao, Yun Qian, Ruizhi Feng
Clinical and Translational Medicine.2025;[Epub] CrossRef - Paxillin/HDAC6 regulates microtubule acetylation to promote directional migration of keratinocytes driven by electric fields
Luojia Liu, Xiaoqiang Liu, Ying Chen, Meng Kong, Jinghong Zhang, Min Jiang, Hongling Zhou, Jinrui Yang, Xu Chen, Ze Zhang, Chao Wu, Xupin Jiang, Jiaping Zhang
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.2024; 1871(2): 119628. CrossRef - Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction
Onsurang Wattanathamsan, Naphat Chantaravisoot, Piriya Wongkongkathep, Sakkarin Kungsukool, Paninee Chetprayoon, Pithi Chanvorachote, Chanida Vinayanuwattikun, Varisa Pongrakhananon
Journal of Biomedical Science.2023;[Epub] CrossRef - Inter-relationship of Histone Deacetylase-6 with Tau-cytoskeletal organization and remodeling
Abhishek Ankur Balmik, Subashchandrabose Chinnathambi
European Journal of Cell Biology.2022; 101(2): 151202. CrossRef - HDAC6 inhibitor, ACY1215 suppress the proliferation and induce apoptosis of gallbladder cancer cells and increased the chemotherapy effect of gemcitabine and oxaliplatin
Yi Ruan, Luoluo Wang, Yeting Lu
Drug Development Research.2021; 82(4): 598. CrossRef - Autophagic degradation of KAT2A/GCN5 promotes directional migration of vascular smooth muscle cells by reducing TUBA/α-tubulin acetylation
Changhan Ouyang, Jing Mu, Qiulun Lu, Jian Li, Huaiping Zhu, Qilong Wang, Ming-Hui Zou, Zhonglin Xie
Autophagy.2020; 16(10): 1753. CrossRef - RASSF1A Regulates Spindle Organization by Modulating Tubulin Acetylation via SIRT2 and HDAC6 in Mouse Oocytes
Hyuk-Joon Jeon, Jeong Su Oh
Frontiers in Cell and Developmental Biology.2020;[Epub] CrossRef - The unraveling of substrate specificity of histone deacetylase 6 domains using acetylome peptide microarrays and peptide libraries
Zsofia Kutil, Lubica Skultetyova, David Rauh, Marat Meleshin, Ivan Snajdr, Zora Novakova, Jana Mikesova, Jiri Pavlicek, Martin Hadzima, Petra Baranova, Barbora Havlinova, Pavel Majer, Mike Schutkowski, Cyril Barinka
The FASEB Journal.2019; 33(3): 4035. CrossRef - Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation
Wenjiao Li, Fei Yue, Yuan Dai, Boyun Shi, Guibin Xu, Xianhan Jiang, Xinke Zhou, Gerd P. Pfeifer, Leyuan Liu
Cell Death & Differentiation.2019; 26(8): 1379. CrossRef - The Role and Function of Ras-association domain family in Cancer: A Review
Mohammad Reza Zinatizadeh, Seyed Ali Momeni, Peyman Kheirandish Zarandi, Ghanbar Mahmoodi Chalbatani, Hassan Dana, Hamid Reza Mirzaei, Mohammad Esmaeil Akbari, Seyed Rouhollah Miri
Genes & Diseases.2019; 6(4): 378. CrossRef - RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis—an updated review
Fatéméh Dubois, Emmanuel Bergot, Gérard Zalcman, Guénaëlle Levallet
Cell Death & Disease.2019;[Epub] CrossRef - Tumor suppressor C-RASSF proteins
Hiroaki Iwasa, Shakhawoat Hossain, Yutaka Hata
Cellular and Molecular Life Sciences.2018; 75(10): 1773. CrossRef - Dual-functionality of RASSF1A overexpression in A375 cells is mediated by activation of IL-6/STAT3 regulatory loop
Mei Yi, Wei Wang, Shengnan Chen, Ya Peng, Junjun Li, Jing Cai, Ying Zhou, Qian Peng, Yuanyuan Ban, Zhaoyang Zeng, Xiaoling Li, Wei Xiong, Guiyuan Li, Bo Xiang
Molecular Biology Reports.2018; 45(5): 1277. CrossRef - Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells
Sarandeep S.S. Boyanapalli, Wenji Li, Francisco Fuentes, Yue Guo, Christina N. Ramirez, Ximena-Parades Gonzalez, Douglas Pung, Ah-Ng Tony Kong
Pharmacological Research.2016; 114: 175. CrossRef - The Potential of Histone Deacetylase Inhibitors in Breast Cancer Therapy
Namita Chatterjee, Martin Tenniswood
Breast Cancer Management.2015; 4(2): 85. CrossRef - CpG site-specific RASSF1a hypermethylation is associated with occupational PAH exposure and genomic instability
Zhini He, Huawei Duan, Biao Zhang, Miao Li, Liping Chen, Bo Zhang, Xiaonian Zhu, Chen Gao, Jie Li, Xiao Zhang, Jingmaio Zhang, Shan Wang, Xiaowen Zeng, Daochuan Li, Xiumei Xing, Zhengbao Zhang, Lu Ma, Qing Bai, Caixia Liu, Yongmei Xiao, Yuxin Zheng, Wen C
Toxicology Research.2015; 4(4): 848. CrossRef - Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity
Christopher Arnette, Nadia Efimova, Xiaodong Zhu, Geoffrey J. Clark, Irina Kaverina, Erika Holzbaur
Molecular Biology of the Cell.2014; 25(6): 800. CrossRef - RASSF tumor suppressor gene family: Biological functions and regulation
Natalia Volodko, Marilyn Gordon, Mohamed Salla, Haya Abu Ghazaleh, Shairaz Baksh
FEBS Letters.2014; 588(16): 2671. CrossRef - MicroRNA expression profiling in male and female familial breast cancer
R Pinto, S De Summa, K Danza, O Popescu, A Paradiso, L Micale, G Merla, O Palumbo, M Carella, S Tommasi
British Journal of Cancer.2014; 111(12): 2361. CrossRef
- Pathogenic variants of TUBB8 cause oocyte spindle defects by disrupting with EB1/CAKP5 interactions and potential treatment targeting microtubule acetylation through HDAC6 inhibition
- 13,232 View
- 138 Download
- 19 Crossref
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No Association between Promoter Polymorphism of
STK11 Gene and Lung Cancer Risk in the Korean Population - Jae Sook Sung, Young Mi Whang, Kyong Hwa Park, Jeong-Seon Ryu, Jong Gwon Choi, Jae Hong Seo, Sang Won Shin, Jun Suk Kim, Yeul Hong Kim
- Cancer Res Treat. 2009;41(4):211-217. Published online December 31, 2009
- DOI: https://doi.org/10.4143/crt.2009.41.4.211
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Abstract
PDFPubReaderePub
Purpose Serine-threonine kinase11 (
STK11 ) was originally identified in 1997 as the causative mutation that's responsible for Peutz-Jeghers Syndrome (PJS). Several recent studies have reported that theSTK11 gene is an important human tumor suppressor gene in lung cancer. We evaluated the associations between the polymorphisms of theSTK11 promoter region and the risk of lung cancer in 901 Koreans.Materials and Methods By direct sequencing, we first discovered three novel polymorphisms (-1,795 T>C, -981 C>T and -160 G>T) and four known polymorphisms (-1,580 C>T, -1,494 A>C, -881 A>G and -458 G>C) of the
STK11 promoter region in 24 blood samples of 24 Korean lung cancer patients. Further genotype analyses were then performed on 443 lung cancer patients and 458 controls.Results We discovered three novel polymorphisms and we identified four known polymorphisms of the
STK11 promoter region in a Korean population. Statistical analyses revealed that the genotypes and haplotypes in theSTK11 gene were not significantly associated with the risk of lung cancer in a Korean population.Conclusion This is the first study that's focused on the association of
STK11 promoter polymorphisms and the risk of lung cancer in a Korean population. To evaluate the role of theSTK11 gene for the risk of lung cancer, the genotypes of theSTK11 promoter region (-1,795 T>C, -1,494 A>C and -160 G>T) were determined in 901 Koreans, yet the result revealed no significant difference between the lung cancer patients and the controls. These results suggest that the three promoter polymorphisms we studied are not important risk factors for the susceptibility to lung cancer in Koreans.-
Citations
Citations to this article as recorded by- A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility
Se-Lyun Yoon, Yun-Gil Roh, In-Sun Chu, Jeonghoon Heo, Seung Il Kim, Heekyung Chang, Tae-Hong Kang, Jin Woong Chung, Sang Seok Koh, Vladimir Larionov, Sun-Hee Leem
Experimental & Molecular Medicine.2016; 48(7): e246. CrossRef - Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D
Ningning He, Nayoung Kim, Mee Song, Choa Park, Somin Kim, Eun Young Park, Hwa Young Yim, Kyunga Kim, Jong Hoon Park, Keun Il Kim, Fan Zhang, Gordon B. Mills, Sukjoon Yoon
Molecular Cancer Therapeutics.2014; 13(10): 2463. CrossRef - Hot embossed polyethylene through-hole chips for bead-based microfluidicdevices
Jie Chou, Nan Du, Tina Ou, Pierre N. Floriano, Nicolaos Christodoulides, John T. McDevitt
Biosensors and Bioelectronics.2013; 42: 653. CrossRef - Discovery and Evaluation of Polymorphisms in theAKT2andAKT3Promoter Regions for Risk of Korean Lung Cancer
Jae Sook Sung, Kyong Hwa Park, Seung Tae Kim, Yeul Hong Kim
Genomics & Informatics.2012; 10(3): 167. CrossRef
- A polymorphic minisatellite region of BORIS regulates gene expression and its rare variants correlate with lung cancer susceptibility
- 10,491 View
- 49 Download
- 4 Crossref
- AKAP12α is Associated with Promoter Methylation in Lung Cancer
- Ukhyun Jo, Young Mi Whang, Han Kyeom Kim, Yeul Hong Kim
- Cancer Res Treat. 2006;38(3):144-151. Published online June 30, 2006
- DOI: https://doi.org/10.4143/crt.2006.38.3.144
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Abstract
PDFPubReaderePub
Purpose Promoter methylation is an important mechanism for silencing tumor-suppressor genes in cancer and it is a promising tool for the development of molecular biomarkers. The purpose of the present study was to investigate whether inactivation of the A Kinase Anchoring Protein 12 (AKAP12) gene is assoCiated with promoter methylation in lung cancer.
Materials and Methods The AKAP12 expression was examined by reverse transcription-polymerase chain reaction (RT-PCR) in ten lung cancer cell lines. The methylation status of the AKAP12α promoter was analyzed by performing bisulfite sequencing analysis in ten lung cancer cell lines, twenty four lung tissues and matched normal tissues.
Results The AKAP12α expression was reduced in 6 of 10 (60%) lung cancer cell lines, whereas the AKAP12β expression was absent in 1 of 10 (10%) lung cancer cell lines. The AKAP12α expression was restored after treatment with the demethylating agent 5-aza-2'-deoxycytidine in three lung cancer cell lines. Methylation of CpG island 1 in the AKAP12α promoter was detected in 30% of the lung cancer cell lines, whereas methylation of CpG island 2 in the AKAP12α promoter was observed in the immortalized bronchial cell line and in all the lung cancer cell lines. In lung tumors, the CpG island 1 in the AKAP12α promoter was infrequently methylated. However, CpG island 2 in the AKAP12α promoter was highly methylated in lung tumors compared with the surrounding normal tissues, and this was statistically significant (p=0.0001).
Conclusion Our results suggest that inactivation of the AKAP12α expression is assoCiated with DNA methylation of the promoter region in lung cancer, and that AKAP12α may play an important role in lung cancer carcinogenesis.
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Citations
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Ke Li, Xuan Wu, Yuan Li, Ting-Ting Hu, Weifeng Wang, Frank J. Gonzalez, Weiwei Liu
Clinical and Translational Oncology.2023; 25(11): 3263. CrossRef - Metastasis suppressor genes in clinical practice: are they druggable?
Irwin H. Gelman
Cancer and Metastasis Reviews.2023; 42(4): 1169. CrossRef - FGF10 Triggers De Novo Alveologenesis in a Bronchopulmonary Dysplasia Model: Impact on Resident Mesenchymal Niche Cells
Sara Taghizadeh, Cho-Ming Chao, Stefan Guenther, Lea Glaser, Luisa Gersmann, Gabriela Michel, Simone Kraut, Kerstin Goth, Janine Koepke, Monika Heiner, Ana Ivonne Vazquez-Armendariz, Susanne Herold, Christos Samakovlis, Norbert Weissmann, Francesca Ricci,
Stem Cells.2022; 40(6): 605. CrossRef - Identifying General Tumor and Specific Lung Cancer Biomarkers by Transcriptomic Analysis
Beatriz Andrea Otálora-Otálora, Daniel Alejandro Osuna-Garzón, Michael Steven Carvajal-Parra, Alejandra Cañas, Martín Montecino, Liliana López-Kleine, Adriana Rojas
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Erica Reggi, Dario Diviani
Cellular Signalling.2017; 40: 143. CrossRef - Elevated AKAP12 in Paclitaxel-Resistant Serous Ovarian Cancer Cells Is Prognostic and Predictive of Poor Survival in Patients
Nicholas W. Bateman, Elizabeth Jaworski, Wei Ao, Guisong Wang, Tracy Litzi, Elizabeth Dubil, Charlotte Marcus, Kelly A. Conrads, Pang-ning Teng, Brian L. Hood, Neil T. Phippen, Lisa A. Vasicek, William P. McGuire, Keren Paz, David Sidransky, Chad A. Hamil
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Irwin H. Gelman
Cancer and Metastasis Reviews.2012; 31(3-4): 493. CrossRef - CancerMA: a web-based tool for automatic meta-analysis of public cancer microarray data
Julia Feichtinger, Ramsay J. McFarlane, Lee D. Larcombe
Database.2012;[Epub] CrossRef - The angiogenesis suppressor gene AKAP12 is under the epigenetic control of HDAC7 in endothelial cells
Andrei Turtoi, Denis Mottet, Nicolas Matheus, Bruno Dumont, Paul Peixoto, Vincent Hennequière, Christophe Deroanne, Alain Colige, Edwin De Pauw, Akeila Bellahcène, Vincent Castronovo
Angiogenesis.2012; 15(4): 543. CrossRef - Mitochondrial Proteomic Analysis of Cisplatin Resistance in Ovarian Cancer
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Journal of Proteome Research.2012; 11(9): 4605. CrossRef - Akap12
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PLoS ONE.2011; 6(4): e18538. CrossRef
- AKAP12 promotes cancer stem cell-like phenotypes and activates STAT3 in colorectal cancer
- 9,917 View
- 55 Download
- 13 Crossref
- Retinoic Acid Enhances Drug-Induced Cell Death in Anticancer Drug-Resistant Cell Lines
- Young Mi Whang, Yeul Hong Kim, Sang Won Shin, Byung Soo Kim, Jun Suk Kim, Young Do Yoo, Sun Hee Park
- Cancer Res Treat. 2002;34(3):212-217. Published online June 30, 2002
- DOI: https://doi.org/10.4143/crt.2002.34.3.212
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Abstract
PDF
- PURPOSE
Retinoids (RA), a group of vitamin A derivatives, is known to be important for regulation of normal cellular growth and differentiation. RA treatment of various cancers resulted in cell growth inhibition and apoptosis. Therefore, the chemotherapeutic and chemopreventative activities of various types of tumor have been examined. Biological actions of RA are mediated through nuclear receptors, including the retinoic acid receptors (RARs) and retinoid X receptors (RXRs). In this study, we examined the effect of all-trans-retinoic acid (atRA) as an anticancer drug-sensitiser in cancer cell lines and in its drug- resistant cancer cell lines MATERIALS AND METGODS: Cells were maintained by RPMI 1640 medium containing 10% fetal bovine serum. Cells were treated with 1 micro M atRA for 48 h, then with the desired concentration of anticancer drug for 24 h. Cell viability was measured spectrophotometrically at 540 nm using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay. Western blot analyses were performed with the desired antibodies.
RESULTS
We investigated if pre-treatment with atRA enhanced the drug-sensitivity of various cancer cell lines to either 5-fluorouracil, adriamycin, or cisplatin. 5-FU (SNU638-F2) and CDDP-resistant cell (SNU638-Cis) lines, from a Korean gastric cancer cell line (SNU638) and the ADR-resistant cells (AD600) was established from a colon cancer cell line (SW620). Treatment of each cell line, with 1 micro M atRA, prior to drug exposure resulted in enhanced cell death in these cell lines. Furthermore, the effect of atRA on growth inhibition, in each drug-resistant cell line, was more obvious than in their parent cell lines. Increased activity of Transglutaminase II (TgaseII) and cleavage of Poly (ADP-ribose) polymerase (PARP) were also observed (western blot analysis CONCLUSION: Based on our data, we suggest that atRA enhances anticancer drug-induced cell death and reverses the drug-sensitivity of the drug-resistant cancer cell lines. -
Citations
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Bingjie Mei, Junyang Li, Dengfeng Wang, Lu Feng, Jianming Huang, Guonan Zhang
Molecular Cancer Therapeutics.2025; 24(3): 453. CrossRef
- All-trans Retinoic Acid Sensitizes Epithelial Ovarian Cancer to PARP Inhibition after Exposure to Cisplatin
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- 43 Download
- 1 Crossref
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