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Garipov A.,Wistar Institute | Garipov A.,Kazan Federal University | Li H.,Wistar Institute | Bitler B.G.,Wistar Institute | And 4 more authors.
Molecular Cancer Research | Year: 2013

Epithelial ovarian cancer (EOC) accounts for the most gynecologic malignancy-associated deaths in the United States. Enhancer of zeste homolog 2 (EZH2), which silences gene expression through generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3), is often overexpressed in EOCs and has been suggested as a therapeutic target. However, the mechanism underlying EZH2 overexpression in EOCs is unknown. Here, we show that EZH2 is upregulated at the transcription level, and two CCAAT boxes in the proximal regions of the human EZH2gene promoter are critical for its transcription inEOCcells. Indeed, NF-YA, the regulatory subunit of the CCAAT-binding transcription factor NF-Y, is expressed at higher levels in human EOCs than in primary human ovarian surface epithelial (HOSE) cells. In addition, there is a positive correlation between expression of NF-YA and EZH2 in EOCs. Notably, high NF-YA expression predicts shorter overall survival in patients with EOCs. The association of NF-YA with the promoter of the human EZH2 gene is enhanced in human EOC cells compared with primary HOSE cells. Significantly, knockdown of NF-YA downregulates EZH2, decreases H3K27Me3 levels, and suppresses the growth of human EOC cells both in vitro and in a xenograft mouse model. Notably, NF-YA knockdown induces apoptosis ofEOCcells and ectopic EZH2 expression partially rescues apoptosis induced by NF-YA knockdown. Together, these data reveal that NF-Y is a key regulator of EZH2 expression and is required for EOC cell proliferation, thus representing a novel target for developing EOC therapeutics. © 2013 American Association for Cancer Research.

Thapa R.J.,Immune Cell Development and Host Defense Program | Chen P.,Immune Cell Development and Host Defense Program | Cheung M.,Cancer Biology Program | Nogusa S.,Immune Cell Development and Host Defense Program | And 5 more authors.
Molecular Cancer Therapeutics | Year: 2013

Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacologic interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine IFN-g showed the potential to provide lasting remission in several phase I/II trials for advanced RCCs, but subsequent trials, including a multicenter phase III study using IFN-g as a monotherapy for RCCs, were less promising. Notably, these trials were designed to exploit the indirect immunomodulatory effects of IFN-g, whereas its direct antitumor properties-including its ability to trigger programmed cell death in tumors- remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise resistant RCC cells to direct necrotic death by IFN-g. Mechanistically, we show that bortezomib functions, at least in part, by inhibiting prosurvival NF-kB signaling. In the absence of this signal, IFN-g triggers programmed necrosis (or "necroptosis") dependent on the kinase RIP1. When taken together with the observation that NF-kB signaling is elevated in RCCs, these results provide rationale for the combined use of IFN-g and bortezomib in the treatment of metastatic RCCs. Mol Cancer Ther; 12(8); 1568-78. © 2013 AACR.

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