The main objectives of this continuation application are to elucidate the molecular mechanisms by which TSA enhances apoptosis induced by the proteasome inhibitor PS-341 in head and neck squamous cell carcinoma (HNSCC) cells. During the last funding period, we found that the co-treatment of PS-341 and TSA in HNSCC cells synergistically induces apoptosis by increasing the expression of pro-apoptotic gene Noxa. To further understand the molecular mechanisms by which TSA enhances PS-341-induced apoptosis, we propose the following four specific aims:
Aim 1 is to explore the epigenetic mechanisms by which PS- 341/TSA induce Noxa expression in HNSCC cells. We hypothesize PS-341/TSA may modify histone ubiquitination to promote Noxa expression in addition to histone accetylation. We will perform chromatin immunoprecipitation (ChIP) assay to determine how PS-341 modulates ubiquitination of H2A and promotes Noxa expression.
Aim 2 is to determine whether TSA may enhance apoptosis by inhibiting autophagy formation in HNSCC cells. Based on our preliminary studies, we hypothesize that TSA may inhibit autophagy and heat shock responses by targeting cellular HDAC6. We will examine whether TSA reduces PS-341- induced autophagy, thereby enhancing apoptosis. We will examine whether TSA inhibits heat shock protein expression by targeting the transcription factor heat shock factor 1.
Aim 3 is to determine whether PS- 341/TSA potently induce the apoptosis of cancer initiating cells (CICs) in vitro and in vivo. CICs exhibit an intrinsic resistance to chemotherapeutic agents, preventing complete elimination of the tumor. Paradoxically, CICs are difficult to maintain or propagate in vitro which represents a significant barrier to study CICs properties and to screen cancer therapeutic drugs against CICs. To overcome this barrier, we propose to develop a cell model system to study CICs from human HNSCC cell lines. We will examine whether PS- 341/TSA can potently induce apoptosis of CICs in vitro and in vivo.
Aim 4 is to explore whether and how Hippo-YAP signaling modulates PS-341/TSA-induced apoptosis. We will over-express or knock-down YAP in HNSCC cells to determine how YAP modulates PS-341/TSA-induced apoptosis. Our work may help to develop targeting therapy for HNSCC with abnormal activation of YAP signaling. In summary, new findings from this application will have clinical implications for treating HNSCC and may help to develop innovative strategies for human cancer treatment
Head and neck cancer typically presents as a very malignant tumor and is frequently resistant to chemo- therapy. The major goals of this project are to develop new therapy strategies for treating head and neck cancer and to improve efficacy of chemotherapy.
|Ramadoss, S; Guo, G; Wang, C-Y (2017) Lysine demethylase KDM3A regulates breast cancer cell invasion and apoptosis by targeting histone and the non-histone protein p53. Oncogene 36:47-59|
|Chang, Insoon; Wang, Cun-Yu (2016) Inhibition of HDAC6 Protein Enhances Bortezomib-induced Apoptosis in Head and Neck Squamous Cell Carcinoma (HNSCC) by Reducing Autophagy. J Biol Chem 291:18199-209|
|Tang, Eric D; Wang, Cun-Yu (2015) YAP-mediated induction of monoacylglycerol lipase restrains oncogenic transformation. Cell Signal 27:836-40|
|Messadi, Diana V; Younai, Fariba S; Liu, Hong-Hu et al. (2014) The clinical effectiveness of reflectance optical spectroscopy for the in vivo diagnosis of oral lesions. Int J Oral Sci 6:162-7|
|Yu, Fa-Xing; Luo, Jing; Mo, Jung-Soon et al. (2014) Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 25:822-30|
|Li, Jiong; Chen, Xiaohong; Ding, Xiangming et al. (2013) LATS2 suppresses oncogenic Wnt signaling by disrupting ?-catenin/BCL9 interaction. Cell Rep 5:1650-63|
|Ding, Xiangming; Pan, Hongya; Li, Jiong et al. (2013) Epigenetic activation of AP1 promotes squamous cell carcinoma metastasis. Sci Signal 6:ra28.1-13, S0-15|
|Wu, Longtao; Zhao, Jonathan C; Kim, Jung et al. (2013) ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer. Cancer Res 73:6068-79|
|Ding, Xiangming; Park, Serk In; McCauley, Laurie K et al. (2013) Signaling between transforming growth factor ? (TGF-?) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis. J Biol Chem 288:10241-53|
|Puckett, Mary C; Goldman, Erinn H; Cockrell, Lisa M et al. (2013) Integration of apoptosis signal-regulating kinase 1-mediated stress signaling with the Akt/protein kinase B-I?B kinase cascade. Mol Cell Biol 33:2252-9|
Showing the most recent 10 out of 22 publications