CHK2 kinase expression is down-regulated due to promoter methylation in non-small cell lung cancer.
BACKGROUND
CHK2 kinase is a tumor suppressor that plays important role in DNA damage signaling, cell cycle regulation and DNA damage induced apoptosis. CHK2 kinase expression was known to be ubiquitous in mammalian cells. CHK2-/- cells were remarkably resistant to DNA damage induced apoptosis, mimicking the clinical behavior of non-small cell lung cancer to conventional chemo and radiation therapy.


RESULTS
We reported that the CHK2 expression is diminished or absent in both non-small cell lung cancer (NSCLC) cell lines and clinical lung cancer tumor specimens. The absent CHK2 expression in NSCLC was due to hypermethylation of the CHK2 gene promoter, preventing from binding of a transcriptional factor, leading to silence of the CHK2 gene transcription.


CONCLUSIONS
Since the CHK2 null mice showed a remarkable radioresistance, which bear significant similarity to clinical behavior of NSCLC, down-regulation of CHK2 kinase expression by CHK2 gene silencing and methylation in non-small cell lung cancer suggest a critical role of CHK2 kinase in DNA damage induced apoptosis and a novel mechanism of the resistance of NSCLC to DNA damage based therapy.
Zhang
Peilin
P
Department of Pathology, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV 26506-9203, USA. pzhang@hsc.wvu.edu
Wang
Jie
J
Gao
Weiyi
W
Yuan
Bao-Zhu
BZ
Rogers
John
J
Reed
Eddie
E
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D002945:Cisplatin / Q000008:administration & dosage / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D004273:DNA, Neoplasm; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D014157:Transcription Factors; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D002945:Cisplatin