A novel plant homeodomain finger 10-mediated antiapoptotic mechanism involving repression of caspase-3 in gastric cancer cells.
The mechanisms governing tumorigenesis of gastric cancer have been an area of intense investigation. Currently, plant homeodomain (PHD) finger (PHF) proteins have been implicated in both tumor suppression and progression. However, the function of PHF10 has not been well characterized. Here, we show that various levels of PHF10 protein were observed in gastric cancer cell lines. Alteration of PHF10 expression, which is associated with tumor cell growth, may result in apoptosis in gastric cancer cells both in vitro and in vivo. Knockdown of PHF10 expression in gastric cancer cells led to significant induction of caspase-3 expression at both the RNA and protein levels and thus induced alteration of caspase-3 substrates in a time-dependent manner. Moreover, results from luciferase assays indicated that PHF10 acted as a transcriptional repressor when the two PHD domains contained in PHF10 were intact. Combined with previous findings, our data suggest that PHF10 transcriptionally regulates the expression of caspase-3. Finally, by using systematic reporter deletion and chromatin immunoprecipitation assays, we localized a region between nucleotides -270 and -170 in the caspase-3 promoter that was required for the efficient inhibition of caspase-3 promoter activity by PHF10. Collectively, our findings show that PHF10 repressed caspase-3 expression and impaired the programmed cell death pathway in human gastric cancer at the transcriptional level.
Wei
Min
M
Department of General Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
Liu
Bingya
B
Su
Liping
L
Li
Jianfang
J
Zhang
Jun
J
Yu
Yingyan
Y
Yan
Min
M
Yang
Zhongyin
Z
Chen
Xuehua
X
Liu
Jiayun
J
Lv
Xin
X
Nie
Hui
H
Zhang
Qing
Q
Zheng
Zhong
Z
Yu
Beiqin
B
Ji
Jun
J
Zhang
Jianian
J
Zhu
Zhenggang
Z
Gu
Qinlong
Q
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000473:pathology*; D014158:Transcription, Genetic
D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; C552094:PHF10 protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D053148:Caspase 3