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Open AccessArticle

HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer

Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
Chang Gung Institute of Technology, Taoyuan 33302, Taiwan
Nano and Mechanical Measurement Laboratory, Center for Measurement Standards, Industrial Technology Research Institute, HsinChu 31057, Taiwan
Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua 50006, Taiwan
School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Division of Hematology and Oncology, Department of Medicine, Taipei Medical University Hospital, Taipei 11050, Taiwan
Human Epigenomics Center, Department of Life Science, Institute of Molecular Biology and Institute of Biomedical Science, National Chung Cheng University, Chiayi 62102, Taiwan
Department of Pathology, Show Chwan Memorial Hospital, Changhua 50008, Taiwan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(10), 2884;
Received: 27 August 2018 / Accepted: 19 September 2018 / Published: 22 September 2018
(This article belongs to the Special Issue Atomic Force Microscopy for Biological Applications)
Cell stiffness is a potential biomarker for monitoring cellular transformation, metastasis, and drug resistance development. Environmental factors relayed into the cell may result in formation of inheritable markers (e.g., DNA methylation), which provide selectable advantages (e.g., tumor development-favoring changes in cell stiffness). We previously demonstrated that targeted methylation of two tumor suppressor genes, hypermethylated in cancer 1 (HIC1) and Ras-association domain family member 1A (RassF1A), transformed mesenchymal stem cells (MSCs). Here, transformation-associated cytoskeleton and cell stiffness changes were evaluated. Atomic force microscopy (AFM) was used to detect cell stiffness, and immunostaining was used to measure cytoskeleton expression and distribution in cultured cells as well as in vivo. HIC1 and RassF1A methylation (me_HR)-transformed MSCs developed into tumors that clonally expanded in vivo. In me_HR-transformed MSCs, cell stiffness was lost, tubulin expression decreased, and F-actin was disorganized; DNA methylation inhibitor treatment suppressed their tumor progression, but did not fully restore their F-actin organization and stiffness. Thus, me_HR-induced cell transformation was accompanied by the loss of cellular stiffness, suggesting that somatic epigenetic changes provide inheritable selection markers during tumor propagation, but inhibition of oncogenic aberrant DNA methylation cannot restore cellular stiffness fully. Therefore, cell stiffness is a candidate biomarker for cells’ physiological status. View Full-Text
Keywords: DNA methylation; AFM; stiffness; cancer DNA methylation; AFM; stiffness; cancer
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Chen, C.-C.; He, B.-C.; Chen, Y.-L.; Lee, K.-D.; Tung, C.-H.; Hsu, C.-C.; Lin, P.-Y.; Chu, P.-Y.; Leu, Y.-W.; Fu, W.-E.; Hsiao, S.-H. HIC1 and RassF1A Methylation Attenuates Tubulin Expression and Cell Stiffness in Cancer. Int. J. Mol. Sci. 2018, 19, 2884.

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