Regulation of pancreatic tumor cell proliferation and chemoresistance by the histone methyltransferase enhancer of zeste homologue 2.
OBJECTIVE
Enhancer of zeste homologue 2 (EZH2), a histone methyltransferase, plays a key role in transcriptional repression through chromatin remodeling. Our objectives were to determine the expression pattern of EZH2 and to assess the anticancer effect of EZH2 depletion in pancreatic cancer cells.


METHODS
Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the expression pattern of EZH2 in normal pancreas and human pancreatic tumors. We used RNA interference, Western blotting, reverse transcription-PCR, and chromatin immunoprecipitation to study the effect of EZH2 depletion on pancreatic cancer cell proliferation and survival.


RESULTS
We detected nuclear overexpression of EZH2 in pancreatic cancer cell lines and in 71 of 104 (68%) cases of human pancreatic adenocarcinomas. EZH2 nuclear accumulation was more frequent in poorly differentiated pancreatic adenocarcinomas (31 of 34 cases; P<0.001). We found that genetic depletion of EZH2 results in reexpression of p27(Kip1) and decreased pancreatic cancer cell proliferation. Moreover, we showed that EZH2 depletion sensitized pancreatic cancer cells to doxorubicin and gemcitabine, which leads to a significant induction of apoptosis, suggesting that the combination of EZH2 inhibitors and standard chemotherapy could be a superior potential treatment for pancreatic cancer.


CONCLUSIONS
Our results show nuclear accumulation of EZH2 as a hallmark of poorly differentiated pancreatic adenocarcinoma; identify the tumor suppressor p27(Kip1) as a new target gene of EZH2; show that EZH2 nuclear overexpression contributes to pancreatic cancer cell proliferation; and suggest EZH2 as a potential therapeutic target for the treatment of pancreatic cancer.
Ougolkov
Andrei V
AV
Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Bilim
Vladimir N
VN
Billadeau
Daniel D
DD
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D000071221:Enhancer of Zeste Homolog 2 Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D063151:Polycomb Repressive Complex 2; D011496:Protein Methyltransferases / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*
C436291:CDKN1B protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2