Abstract
The role of Pokemon (POK erythroid myeloid ontogenic actor), a recently identified POK transcription factor with proto-oncogenic activity, in hepatocellular carcinogenesis has only been assessed by a few studies. Our previous study revealed that Pokemon is overexpressed in hepatocellular carcinomas (HCC) and promotes HCC cell proliferation and migration via an AKT- and ERK- dependent manner. In the present study, we used the TUNEL assay and FACS analysis to demonstrate that oxaliplatin induced apoptosis was significantly increased in cells with silenced Pokemon. Western blots showed that p53 expression and phosphorylation were significantly increased in Pokemon defective cells, thereby initiating the mitochondria-mediated and death receptor-mediated apoptotic pathways. In the mitochondria-mediated pathway, expression of pro-apoptotic Bcl-2 family members (including Bad, Bid, Bim and Puma) as well as AIF was increased and decreasing the mitochondrial membrane potential resulted in cytochrome C released from mitochondrial in HepG2 si-Pokemon cells. In addition, upon oxaliplatin treatment of Pokemon-silenced cells, the FAS receptor, FADD and their downstream targets caspase-10 and caspase-8 were activated, causing increased release of caspase-8 active fragments p18 and p10. Increased activated caspase-8-mediated cleavage and activation of downstream effector caspases such as caspase-9 and caspase-3 was observed in HepG2 si-Pokemon cells as compared to control. Therefore, Pokemon might serve as an important mediator of crosstalk between intrinsic and extrinsic apoptotic pathways in HCC cells. Moreover, our findings suggest that Pokemon could be an attractive therapeutic target gene for human cancer therapy.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide and is the third leading cause of cancer deaths
Our previous study demonstrated that Pokemon is overexpressed in HCC and promotes HCC cell proliferation and migration via an AKT- and ERK -dependent manner [5]
To further confirm that silencing Pokemon promotes apoptosis, we analyzed cells treated with increasing concentrations of oxaliplatin for 24 hours by FACS
Summary
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide and is the third leading cause of cancer deaths. Fas-associated death domain (FADD) regulates cellular apoptosis in HCC, with loss of FADD expression playing an important role in HCC carcinogenesis [2]. Pokemon (POK erythroid myeloid ontogenic actor), known as FBI-1, LRF and OCZF, has recently been identified as a POK transcription factor with proto-oncogenic activity. It consists of an NH2-terminal POZ/BTB domain and COOH-terminal kruppeltype zinc finger domain [3,4]. Another study demonstrated that Pokemon can regulate cell-cycle progression by repressing Rb and p21 and that its activity is mediated by direct binding competition with the Sp1/3 GC-box [7,8]. Few studies have assessed the role of Pokemon in apoptosis in HCC
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