The main objectives of this continuation application are to elucidate the molecular mechanisms by whichTSA enhances apoptosis induced by the proteasome inhibitor PS-341 in head and neck squamous cellcarcinoma (HNSCC) cells. During the last funding period, we found that the co-treatment of PS-341 and TSAin 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, wepropose 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 histoneubiquitination to promote Noxa expression in addition to histone accetylation. We will perform chromatinimmunoprecipitation (ChIP) assay to determine how PS-341 modulates ubiquitination of H2A and promotesNoxa expression.
Aim 2 is to determine whether TSA may enhance apoptosis by inhibiting autophagyformation in HNSCC cells. Based on our preliminary studies, we hypothesize that TSA may inhibit autophagyand 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 proteinexpression 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 anintrinsic 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 CICsproperties and to screen cancer therapeutic drugs against CICs. To overcome this barrier, we propose todevelop 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 howHippo-YAP signaling modulates PS-341/TSA-induced apoptosis. We will over-express or knock-down YAPin HNSCC cells to determine how YAP modulates PS-341/TSA-induced apoptosis. Our work may help todevelop targeting therapy for HNSCC with abnormal activation of YAP signaling. In summary, new findingsfrom this application will have clinical implications for treating HNSCC and may help to develop innovativestrategies 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 neckcancer and to improve efficacy of chemotherapy.
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