Prolyl hydroxylase-2 inhibits liver tumor cell proliferation and cyclin D1 expression in a hydroxylase-dependent manner

详细信息    查看全文

• 作者：Yifeng Tao^a ; ¹ ; Feng Lin^b ; ¹ ; Ruidong Li^a ; Jie Shen^b ; ^{shenjietzh@126.com" class="auth_mail" title="E-mail the corresponding author} ; Zhengxin Wang^a ; ^{wangzhengxinhsh@163.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：PHD2 ; Cyclin D1 ; Tumor suppressor ; Liver cancer ; Doxycycline
• 刊名：International Journal of Biochemistry and Cell Biology
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：77
• 期：part_PA
• 页码：129-140
• 全文大小：2948 K

文摘

Prolyl hydroxylase 2 is a key regulator of hypoxia-inducible factor 1 alpha protein, and has previously been implicated as a tumor suppressor in various cancers. However, the function of prolyl hydroxylase 2 in liver cancer has yet to be elucidated. Characterization of prolyl hydroxylase 2 function and related mechanisms in liver cancer may enable the development of targeted therapy. Here we found that prolyl hydroxylase 2 overexpression in human hepatocellular carcinoma cancer cell lines inhibited cell proliferation, while prolyl hydroxylase 2 knockdown enhanced cell proliferation. Further analyses revealed that the prolyl hydroxylase 2-mediated inhibition of cell proliferation was due to a cell cycle arrest at the G1/S transition. Moreover, the block in cell cycle was facilitated by negative regulation of cyclin D1, a process dependent on the hydroxylase activity of prolyl hydroxylase 2. Using an in vivo xenograft mouse model, we found that the overexpression of prolyl hydroxylase 2 led to a reduction in tumor size. Evaluation of paired human liver cancer patient samples revealed that prolyl hydroxylase 2 protein levels were significantly reduced in 6 of the 10 cancer tissues as compared to their respective normal tissue controls. Furthermore, elevated expression of prolyl hydroxylase 2 was associated with significantly prolonged survival in patients with liver cancer. These results suggest that prolyl hydroxylase 2 plays an important tumor suppressive role in liver cancer and may prove to be of prognostic and therapeutic value.