15-Hydroxyprostaglandin dehydrogenase is a target of hepatocyte nuclear factor 3beta and a tumor suppressor in lung cancer.
The forkhead transcription factor hepatocyte nuclear factor 3beta (HNF3beta) is essential in foregut development and the regulation of lung-specific genes. HNF3beta expression leads to growth arrest and apoptosis in lung cancer cells and HNF3beta is a candidate tumor suppressor in lung cancer. In a transcriptional profiling study using a conditional cell line system, we now identify 15-PGDH as one of the major genes induced by HNF3beta expression. 15-PGDH is a critical metabolic enzyme of proliferative prostaglandins, an antagonist to cyclooxygenase-2 and a tumor suppressor in colon cancer. We confirmed the regulation of 15-PGDH expression by HNF3beta in a number of systems and showed direct binding of HNF3beta to 15-PGDH promoter elements. Western blotting of lung cancer cell lines and immunohistochemical examination of human lung cancer tissues found loss of 15-PGDH expression in approximately 65% of lung cancers. Further studies using in vitro cell-based assays and in vivo xenograft tumorigenesis assays showed a lack of in vitro but significant in vivo tumor suppressor activity of 15-PGDH via an antiangiogenic mechanism analogous to its role in colon cancer. In summary, we identify 15-PGDH as a direct downstream effector of HNF3beta and show that 15-PGDH acts as a tumor suppressor in lung cancer.
Huang
Guosheng
G
Department of Pathology, Division of Hematology/Oncology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Eisenberg
Rosana
R
Yan
Min
M
Monti
Stefano
S
Lawrence
Earl
E
Fu
Pingfu
P
Walbroehl
Jaclyn
J
Löwenberg
Ester
E
Golub
Todd
T
Merchan
Jaime
J
Tenen
Daniel G
DG
Markowitz
Sanford D
SD
Halmos
Balazs
B
D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D051542:Hepatocyte Nuclear Factor 3-beta; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase