We previously identified SIRT2, an nicotinamide adenine dinucleotide (NAD)-dependent tubulin deacetylase, as a protein downregulated in gliomas and glioma cell lines, which are characterized by aneuploidy. Other studies reported SIRT2 to be involved in mitotic progression in the normal cell cycle. We herein investigated whether SIRT2 functions in the mitotic checkpoint in response to mitotic stress caused by microtubule poisons. By monitoring chromosome condensation, the exogenously expressed SIRT2 was found to block the entry to chromosome condensation and subsequent hyperploid cell formation in glioma cell lines with a persistence of the cyclin B/cdc2 activity in response to mitotic stress. SIRT2 is thus a novel mitotic checkpoint protein that functions in the early metaphase to prevent chromosomal instability (CIN), characteristics previously reported for the CHFR protein.We further found that histone deacetylation, but not the aberrant DNA methylation of SIRT2 5 0 untranslated region is involved in the downregulation of SIRT2. Although SIRT2 is normally exclusively located in the cytoplasm, the rapid accumulation of SIRT2 in the nucleus was observed after treatment with a nuclear export inhibitor, leptomycin B and ionizing radiation in normal human fibroblasts, suggesting that nucleo-cytoplasmic shuttling regulates the SIRT2 function. Collectively, our results suggest that the further study of SIRT2 may thus provide new insights into the relationships among CIN, epigenetic regulation and tumorigenesis. Oncogene (2007) 26, 945-957.

The human chromosome region 11p15.5 contains a number of maternally and paternally imprinted genes, and the LIT1/KCNQ1OT1 locus acts as an imprinting center in the proximal domain of 11p15.5. Loss of imprinting (LOI) of LIT1 and its correlation with methylation status at a differentially methylated region, the KvDMR1, were investigated in 69 colorectal cancer tissue specimens. LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines. In 69 colorectal cancer tissue specimens, LOI of LIT1 was observed in nine of the 17 (53%) informative cases. Moreover, LOI of LIT1 was only observed in tumor samples. In the cell lines, methylation status at the KvDMR1 correlated well with LIT1 expression profiles. Loss of expression of LIT1 also correlated with enrichment of H3 lysine 9 (H3-K9) dimethylation and reduction of H3 lysine 4 (H3-K4) dimethylation. Thus, LIT1 expression appears to be controlled by epigenetic modifications at the KvDMR1, although CDKN1C expression, which is considered to be controlled by LIT1, was not associated with epigenetic status at the KvDMR1 in some colorectal cancer cell lines. Therefore, these findings suggest that LOI of LIT1 via epigenetic disruption plays an important role in colorectal carcinogenesis, but it is not necessarily associated with CDKN1C expression. (Cancer Sci 2006; 97: 1147-1154) G enomic imprinting is an epigenetic modification that leads to the preferential or exclusive expression of a gene from one of the two parental alleles in somatic cells.(1) The imprint, such as DNA methylation and histone modification, is established as the gene passes through the parental germ line and it is reversible. (2)(3)(4) Imprinted genes play important roles in embryonic development as revealed by the highly restricted developmental potential of both androgenotes with two paternal genomes and of either gynogenotes or parthenogenotes with two maternal genomes.(5,6) Abnormal imprinting is also involved in a number of human diseases. In particular, the loss of imprinting (LOI) is one of the most frequent genetic alterations in cancers.(7) LOI is a phenomenon that involves abnormal activation of a normally silent allele. A large amount of evidence suggests that disruption of imprinting mechanisms may play a critical role in the development of cancer. (8,9) Imprinted genes, of which more than 70 have already been identified, tend to be present as a cluster spreading over a mega base of DNA. The genes in the cluster are regulated under the control of long-range regulatory elements. This notion is corroborated by the fact that the differentially methylated regions (DMR) associated with imprinted clusters play a crucial role in maintenance of the parent-of-origin-specific gene expression pattern, which is called an imprinting control region (ICR).The cluster on human chromosome 11p15.5 comprises two ICR. The H19 ICR controls the imprinted gene expression of H19 and IGF2, (10) whereas the KvDMR1 functions by silencing at least eight matern...

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