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

• Published in: International journal of molecular sciences 2018-09, Vol.19 (10), p.2884
• Main Authors: Chen, Chih-Cheng, He, Bo-Ching, Chen, Yao-Li, Lee, Kuan-Der, Tung, Chun-Hsin, Hsu, Chia-Chen, Lin, Ping-Yi, Chu, Pei-Yi, Leu, Yu-Wei, Fu, Wei-En, Hsiao, Shu-Huei
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers, Tumor; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; DNA Methylation; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mesenchymal Stem Cells - metabolism; Mesenchymal Stem Cells - pathology; Mice; Mice, Nude; Prognosis; Promoter Regions, Genetic; Stress, Mechanical; Tubulin - genetics; Tubulin - metabolism; Tumor Cells, Cultured; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms19102884

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 ( ) and Ras-association domain family member 1A ( ), 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. and methylation ( )-transformed MSCs developed into tumors that clonally expanded in vivo. In -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, -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.