Prolyl hydroxylase-2 inhibits liver tumor cell proliferation and cyclin D1 expression in a hydroxylase-dependent manner.
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.
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Yifeng
Y
Tao
Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, China.
Feng
F
Lin
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
Ruidong
R
Li
Department of General Surgery, Taizhou First People's Hospital, Taizhou, Zhejiang 318020, China. Electronic address: shenjietzh@126.com.
Jie
J
Shen
Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200040, China. Electronic address: wangzhengxinhsh@163.com.
Zhengxin
Z
Wang
D017209:Apoptosis; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics*; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology*; D016196:S Phase
D019938:Cyclin D1; C490190:EGLN1 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases
Cyclin D1; Doxycycline; Liver cancer; PHD2; Tumor suppressor