Lsh-deficient murine embryonal fibroblasts show reduced proliferation with signs of abnormal mitosis

T Fan, Q Yan, J Huang, S Austin, E Cho, D Ferris… - Cancer research, 2003 - AACR
T Fan, Q Yan, J Huang, S Austin, E Cho, D Ferris, K Muegge
Cancer research, 2003AACR
Genomic hypomethylation and chromosomal instability are frequent characteristics of
human cancer cells. Targeted deletion of Lsh leads to a global defect in genomic
methylation, and Lsh-deficient mice die at birth with a reduced body weight. Here, we
examine the growth pattern of embryonal fibroblasts derived from Lsh−/− mice. The absence
of Lsh leads to a severe proliferative defect of fibroblasts with lower saturation density, early
signs of senescence, and a lower frequency of immortalization. The impaired growth rate in …
Abstract
Genomic hypomethylation and chromosomal instability are frequent characteristics of human cancer cells. Targeted deletion of Lsh leads to a global defect in genomic methylation, and Lsh-deficient mice die at birth with a reduced body weight. Here, we examine the growth pattern of embryonal fibroblasts derived from Lsh−/− mice. The absence of Lsh leads to a severe proliferative defect of fibroblasts with lower saturation density, early signs of senescence, and a lower frequency of immortalization. The impaired growth rate in vitro may be in part responsible for the small size of Lsh-deficient mice. In addition, Lsh−/− fibroblasts accumulated high centrosome numbers, formed multipolar spindles, displayed micronuclei formation, and elevated nuclear DNA content. A similar increase in centrosome abnormalities was observed when wild-type fibroblasts were treated with a DNA-demethylating agent, suggesting that genomic hypomethylation plays an important role in mitotic defects of Lsh−/− murine embryonal fibroblasts, possibly by altering chromatin structure. Because supernumerary centrosomes are a common feature in cancer cells, this Lsh-dependent pathway has the potential to contribute to genetic instability and chromosomal aberrations during tumor progression.
AACR