Characterization of loss-of-inactive X in Klinefelter syndrome and female-derived cancer cells

Abstract

The increased risk of several types of cancer in Klinefelter syndrome (47XXY) suggests that the extra X chromosome may be involved in the tumorigenesis associated with this syndrome. Here, we show that cancer cells (PSK-1) derived from a patient with Klinefelter syndrome (47XXY) showing loss of an inactive X chromosome subsequently gained active X chromosomes. We found that this abnormal X chromosome composition in PSK-1 is caused by a loss of an inactive X chromosome followed by multiplication of identical active X chromosomes, not by reactivation of an inactive X chromosome. Furthermore, we extended the characterization of loss-of-inactive X in a series of 22 female-derived cancer cell lines (eight breast cancer cell lines, seven ovarian cancer cell lines, and seven cervical cancer cell lines). The data demonstrate that lossof-inactive X in the female-derived cancer cells is mainly achieved by loss of an inactive X chromosomes followed by multiplication of an identical active X chromosomes. However, distinctive pathways, including reactivation of an inactive X chromosome, are also involved in the mechanisms for loss-of-inactive X and gain-of-active X in female-derived cancer cells. The biological significance of the loss-of-inactive X and gain-of-active X in the oncogenesis of Klinefelter syndrome and female-derived cancer cells are discussed.

X Chromosome Inactivation and Breast Cancer: Epigenetic Alteration in Tumor Initiation and Progression

“…The absence of XIST RNA in these tumors therefore does not indicate a role for BRCA1 in regulating XIST RNA localization. Instead, the data presented in support the interpretation that loss of XIST RNA in cancer is often due to loss of the Xi, as is well documented (Sirchia et al, 2005;Kawakami et al, 2004) and as is supported by our analysis of murine Brca1 tumors. reported that depletion of BRCA1 by RNAi caused infrequent reactivation of an Xi-linked GFP transgene and attributed this low-level reactivation to loss of Xist RNA.…”

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

“…We demonstrated that three X-linked genes (AR, FMR1 and GPC3) on supernumerical X-chromosomes in both seminomatous and non-seminomatous TGCTs are predominantly unmethylated, regardless of whether XIST is expressed (Kawakami et al, 2003). The data indicate that the roles of XIST expression in TGCTs are distinct from those in female-inactive X-chromosomes where the X-linked genes (AR, FMR1 and GPC3) are silenced via methylation of the promoter (Allen et al, 1992;Kirchgessner et al, 1995;Huber et al, 1999;Kawakami et al, 2004b). We have also shown that the unmethylated profile is present at the 5 0 end of the XIST gene in both seminomatous and non-seminomatous TGCTs, regardless of XIST expression (Kawakami et al, 2004a).…”

Sexual dimorphism in cancer

“…Although inactivation of one X chromosome over the other is generally random, preferential inactivation of one chromosome (skewed Xi) can protect women against the consequences of X-linked gene mutations 104 . On the contrary the absence of Xi can have detrimental effects: for instance loss of Xist has been reported in breast, ovarian and cervical cancer cell lines 105,106 and, only in female mutant mice, it caused deregulation of hematopoietic lineages and emergence of myeloid neoplasms associated with genome wide changes in gene expression 107 .…”