Abstract 962: Deregulated transcription of mouse satellite sequences accelerates oncogenic processes via functional inhibition of YBX1 protein

Abstract

Abstract Highly repetitive tandem arrays located at centromere and pericentromere regions of the chromosomes had been considered epigenetically silent by heterochromatin modification. However, the deregulated transcription of the non-coding satellite sequences exists in human and mouse pancreatic cancer tissues. This aberrant expression can be detected even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are pre-cancerous lesions to invasive pancreatic cancer. To examine the biological roles of these aberrantly expressed satellite RNAs during the carcinogenesis steps, we established genetically-modified mouse PanIN-derived cells, in which mouse major satellite (MajSAT) RNAs were ectopically expressed. MajSAT RNA expressing PanIN-derived cells showed the increased chromosomal instability and the rate of spontaneous point mutations in the genomic as well as in the mitochondrial DNAs. We identified YBX1 protein as a binding protein specifically with MajSAT RNA by RNA immunoprecipitation. MajSAT RNA inhibited nuclear translocation of YBX1 under oxidative damage, which reduced the DNA damage repair activity of YBX1. The mutation rate of genomic and mitochondrial DNAs, and transformation rate were rescued by YBX1 overexpression in these cells. These findings indicate that satellite transcripts at the early stage of cancer development may act as “mutagens” and accelerate oncogenic processes. Citation Format: Takahiro Kishikawa, Motoyuki Otsuka, Kazuhiko Koike. Deregulated transcription of mouse satellite sequences accelerates oncogenic processes via functional inhibition of YBX1 protein. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 962.