Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter. Total RNA obtained from cells overexpressed HDAC4 cDNA in MCF-7 compared to control cells.
Project description:HDACs play crucial role in epigenetic modulation through deacetylation of histone and non-histone substrates in critical process of normal development and cancer. Moreover, HDAC inhibitors have been considered as new agent by effects such as cell cycle arrest, apoptosis, anti-angiogenic effects and autophagy and utilized in clinical applications for chemotherapy. we previously reported that HDAC 1, 4, 6 and 8 were higly expressed in MDA-MB-231 than MCF-7 cells and HDAC1, 6 and 8 excepting HDAC4 were associated with invasion that is very important factor in cancer progression. However, HDAC4 did not affect in invasion. To investigate interaction between chemoresistance and HDAC4 expression, we establish stable cells overexpressing HDAC4 in MCF-7 cells. Cells overexpressed HDAC4 were increased cytotoxicity about 5-FU and identified 356 differentially expressed genes using Ilumina array. Based on array result, we selected SMAD4 as a candidate gene related with chemoresistance because SMAD4 was previously reported evaluation of chemoresistance to 5-FU. We purpose that HDAC4 regulated with SMAD4 expression through acetylation in SMAD4 promoter region. HDAC4 directly bound a part of SMAD4 promoter.
Project description:Bone defects in the craniofacial region, such as mandibular critical-sized defects (CSDs), represent a significant clinical challenge due to the limited self-healing capacity and shortcomings of current therapeutic options. Bone tissue engineering using human adipose-derived stem cells (hASCs) offers a promising alternative. This study investigates the role of histone deacetylase 4 (HDAC4) and its inhibition as a therapeutic strategy in regulating hASCs osteogenic differentiation via histone acetylation. Using CUT&Tag sequencing, we identified HDAC4-regulated histone acetylation sites that modulate the expression of osteogenesis-related factors, including the key transcription factor SMAD4. HDAC4 knockdown enhanced histone acetylation, promoted SMAD4 expression, and significantly improved osteogenic differentiation of hASCs. These findings were further validated in vivo using calvarial and mandibular defect models in nude mice. As an alternative inhibition strategy, the selective HDAC4 inhibitor Tasquinimod (Tasq) was evaluated. At 1 µM, Tasq enhanced hASCs proliferation, promoted histone acetylation, upregulated SMAD4, and stimulated osteogenic differentiation markers (ALP, OSX, COL1A1), mimicking the effects of HDAC4 knockdown. To enable localized delivery, a Tasq-loaded GelMA-F127 composite hydrogel was developed. This hydrogel exhibited excellent mechanical properties, biocompatibility, and sustained release. Applied to mandibular defects, GelMA-F127-Tasq significantly enhanced bone regeneration. In conclusion, this study elucidates the epigenetic mechanisms of HDAC4 in hASCs osteogenesis and highlights the potential of Tasq-loaded hydrogels as a therapeutic strategy for bone defect repair.
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
Project description:Transcriptional profiling of human mesenchymal stem cells comparing normoxic MSCs cells with hypoxic MSCs cells. Hypoxia may inhibit senescence of MSCs during expansion. Goal was to determine the effects of hypoxia on global MSCs gene expression.