Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma.
LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle, but their methylation statuses are still unknown in human astrocytoma. Here, we found that the promoter hypermethylation frequencies of LATS1 and LATS1 were 63.66% (56/88) and 71.5% (63/88) in 88 astrocytomas by methylation-specific PCR. But no methylation of LATS1 and LATS2 promoter was detected in the 10 normal brain tissues. There was an increased methylation frequency of LATS1 and LATS2 with the malignant development of astrcytoma. By real-time PCR, the mRNA expression of LATS1 or LATS2 was detected significantly decreased in different pathological grade astrocytomas (P<0.05). And the mRNA levels of LATS1 and LATS2 in astrocytomas with hypermethylation were both significantly (P<0.01) lower than those without methylation. The methylation of LATS1 and LATS2 was detected in U251 and SHG-44 cell lines, and 5-aza-deoxycytidine could restore their expression to induce cell apoptosis. Our results suggested that LATS1 and LATS2 mRNA was down-regulated in astrocytoma by hypermethylation of the promoter. The methylation and mRNA expression of LATS1 and LATS2 may provide useful clues to the development of the diagnostic assays for astrocytoma. Our results also suggested that LATS1 and LATS2 may be a useful target for astrocytoma therapy.
Jiang
Zheng
Z
Laboratory of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China. drjiangzheng@hotmail.com
Li
Xingang
X
Hu
Jin
J
Zhou
Wei
W
Jiang
Yuquan
Y
Li
Gang
G
Lu
Daru
D
D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism*; D001374:Azacitidine / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D003640:Dealkylation; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013431:Sulfates / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013431:Sulfates; D025521:Tumor Suppressor Proteins; C012036:sodium sulfate; D004247:DNA; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D001374:Azacitidine