SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

Tan A Nguyen; Kathryn T Bieging-Rolett; Tracy L Putoczki; Ian P Wicks; Laura D Attardi; Ken C Pang

doi:10.1016/j.isci.2019.09.009

SIDT2 RNA Transporter Promotes Lung and Gastrointestinal Tumor Development

iScience. 2019 Oct 25:20:14-24. doi: 10.1016/j.isci.2019.09.009. Epub 2019 Sep 10.

Authors

Tan A Nguyen¹, Kathryn T Bieging-Rolett², Tracy L Putoczki¹, Ian P Wicks¹, Laura D Attardi², Ken C Pang³

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
² Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
³ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Murdoch Children's Research Institute, Parkville, VIC, Australia; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia; Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia. Electronic address: ken.pang@mcri.edu.au.

Abstract

RNautophagy is a newly described type of selective autophagy whereby cellular RNAs are transported into lysosomes for degradation. This process involves the transmembrane protein SIDT2, which transports double-stranded RNA (dsRNA) across the endolysosomal membrane. We previously demonstrated that SIDT2 is a transcriptional target of p53, but its role in tumorigenesis, if any, is unclear. Unexpectedly, we show here that Sidt2^-/- mice with concurrent oncogenic Kras^G12D activation develop significantly fewer tumors than littermate controls in a mouse model of lung adenocarcinoma. Consistent with this observation, loss of SIDT2 also leads to enhanced survival and delayed tumor development in an Apc^min/+ mouse model of intestinal cancer. Within the intestine, Apc^min/+;Sidt2^-/- mice display accumulation of dsRNA in association with increased phosphorylation of eIF2α and JNK as well as elevated rates of apoptosis. Taken together, our data demonstrate a role for SIDT2, and by extension RNautophagy, in promoting tumor development.

Keywords: Biological Sciences; Cancer; Cell Biology; Molecular Biology.

Grants and funding

R35 CA197591/CA/NCI NIH HHS/United States