Deciphering the Nuclear Localization and Regulation of Neochromosomes in Liposarcoma

Abstract

Soft tissue sarcomas are rare and cancers arising from transformed cells of mesenchymal origin. Liposarcoma accounts for ~20 % of soft tissue sarcomas and are aggressive, partly treatment resistant tumours with high mortality rate. Well-differentiated and dedifferentiated liposarcomas are the most common sub-types of liposarcoma and are characterized by the presence of cancer specific chromosomes, termed neochromosomes, that consists of amplifications covering oncogenes such as MDM2, CDK4 and HMGA2. Gene expression levels in these amplified regions do not correlate well with the number of amplifications observed in such cancers. Moreover, where these cancer specific chromosomes are located within the nucleus and how they are regulated in the cancer cells are unknown. Here, we show that neochromosomes localize to the nuclear periphery in the interphase nucleus of three liposarcoma cell lines by 3D-immunoFISH. We observe significant upregulation of lamin A/C and lamin B1 in the cancer cells. We also report globally elevated levels of the repressive histone mark H3K27me3 and upregulation of expression of the histone methyltransferase EZH2. Collectively, these results enabled us to establish a working hypothesis of how amplified oncogenic regions found in neochromosomes could be regulated at the nuclear periphery, where peripheral targeting is generally associated with heterochromatin and gene silencing.