The JmjC domain-containing histone demethylase KDM3A is a positive regulator of the G1/S transition in cancer cells via transcriptional regulation of the HOXA1 gene.
A number of histone demethylases have been identified and biochemically characterized, yet their biological functions largely remain uncharacterized, particularly in the context of human diseases such as cancer. In this study, we describe important roles for the histone demethylase KDM3A, also known as JMJD1A, in human carcinogenesis. Expression levels of KDM3A were significantly elevated in human bladder carcinomas compared with nonneoplastic bladder tissues (p < 0.0001), when assessed by real-time PCR. We confirmed that some other cancers including lung cancer also overexpressed KDM3A, using cDNA microarray analysis. Treatment of cancer cell lines with small interfering RNA targeting KDM3A significantly knocked down its expression and resulted in the suppression of proliferation. Importantly, we found that KDM3A activates transcription of the HOXA1 gene through demethylating histone H3 at lysine 9 di-methylation by binding to its promoter region. Indeed, expression levels of KDM3A and HOXA1 in several types of cancer cell lines and bladder cancer samples were statistically correlated. We observed the down-regulation of HOXA1 as well as CCND1 after treatment with KDM3A siRNA, indicating G(1) arrest of cancer cells. Together, our results suggest that elevated expression of KDM3A plays a critical role in the growth of cancer cells, and further studies may reveal a cancer therapeutic potential in KDM3A inhibition.
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
Hyun-Soo
HS
Cho
Gouji
G
Toyokawa
Yataro
Y
Daigo
Shinya
S
Hayami
Ken
K
Masuda
Noriko
N
Ikawa
Yuka
Y
Yamane
Kazuhiro
K
Maejima
Tatsuhiko
T
Tsunoda
Helen I
HI
Field
John D
JD
Kelly
David E
DE
Neal
Bruce A J
BA
Ponder
Yoshihiko
Y
Maehara
Yusuke
Y
Nakamura
Ryuji
R
Hamamoto
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008745:Methylation; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099261:Homeobox A1 Protein
D019938:Cyclin D1; D006657:Histones; D018398:Homeodomain Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C530104:CCND1 protein, human; C530247:KDM3A protein, human