Satellite RNAs promote pancreatic oncogenic processes via the dysfunction of YBX1

Takahiro Kishikawa, Motoyuki Otsuka (), Takeshi Yoshikawa, Motoko Ohno, Hideaki Ijichi and Kazuhiko Koike
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Takahiro Kishikawa: Graduate School of Medicine, The University of Tokyo
Motoyuki Otsuka: Graduate School of Medicine, The University of Tokyo
Takeshi Yoshikawa: Graduate School of Medicine, The University of Tokyo
Motoko Ohno: Graduate School of Medicine, The University of Tokyo
Hideaki Ijichi: Graduate School of Medicine, The University of Tokyo
Kazuhiko Koike: Graduate School of Medicine, The University of Tokyo

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA. We identify Y-box binding protein 1 (YBX1) as a protein that binds to MajSAT RNA. MajSAT RNA inhibits the nuclear translocation of YBX1 under stress conditions, thus reducing its DNA-damage repair function. The forced expression of YBX1 significantly decreases the aberrant phenotypes. These findings indicate that during the early stage of cancer development, satellite transcripts may act as ‘intrinsic mutagens’ by inducing YBX1 dysfunction, which may be crucial in oncogenic processes.

Date: 2016
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DOI: 10.1038/ncomms13006

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