Epigenetic regulation of the potential tumor suppressor gene, hLHX6.1, in human cervical cancer.
It is well known that the Homo sapiens LIM homeobox domain 6 gene (hLHX6), a putative transcription regulator, controls the differentiation and development of neural and lymphoid cells, particularly in the central nervous system. In this study, we investigated hLHX6.1 (an isoform of hLHX6), which functions as a tumor suppressor gene in the cervix. Firstly, the methylation levels of the hLHX6 and hLHX6.1 promoters were investigated in 8 cervical cancer cell lines and human tissue samples with a distinctive degree of malignant transformation. In spite of the presence of multiple cytosine guanine dinucleotides (CpG islands) in 2 proximal promoters of the hLHX6 and hLHX6.1 genes, only the hLHX6.1 promoters were found to be mostly hypermethylated and associated with transcriptional silencing by promoter methylation, whereas the hLHX6 promoters were not. Methylation levels in the hLHX6.1 promoter were also found to be strongly related to cervical cancer development. The level of hLHX6.1 gene expression was found to be relatively high in normal cells, in which the hLHX6.1 promoter was mostly unmethylated. However, the hLHX6.1 gene expression was down-regulated or undetectable in cervical cancer cell lines and cancer tissues, in which the hLHX6.1 promoter was hypermethylated. This epigenetic alteration in the hLHX6.1 promoter begins at a relatively early stage, suggesting its potential as a biomarker for the early diagnosis and prevention of cervical cancer. Moreover, the overexpression of the hLHX6.1 gene in cervical cancer cells suppressed the tumorigenic phenotype, as shown by soft agar colony formation and migration assays, suggesting that hLHX6.1 could be a new tumor suppressor gene in the cervix.
Research Center for Women's Diseases, Division of Biological Sciences, Sookmyung Women's University, Seoul, Republic of Korea.
Samil
S
Jung
Dongjun
D
Jeong
Jinsun
J
Kim
Lisha
L
Yi
Keunhoe
K
Koo
Jaehyouk
J
Lee
Chang-Jin
CJ
Kim
Chang-Hwan
CH
Kim
Sungwhan
S
An
Young
Y
Yang
Jong-Seok
JS
Lim
Keun Il
KI
Kim
Myeong-Sok
MS
Lee
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000473:pathology; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000235:genetics / Q000473:pathology
D018398:Homeodomain Proteins; C121947:LHX6 protein, human; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors