Ferro, Iolanda; Gavini, Jacopo; Gallo, Stefano; Bracher, Lisamaria; Landolfo, Marc; Candinas, Daniel; Keogh-Stroka, Deborah M.; Polacek, Norbert (2021). The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome in hepatocellular carcinoma. Autophagy, 18(1), pp. 191-203. Landes Bioscience 10.1080/15548627.2021.1922983
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Ferro__Gavini_et_al_Autophagy_2022.pdf - Published Version Available under License Creative Commons: Attribution-Noncommercial-No Derivative Works (CC-BY-NC-ND). Download (3MB) | Preview |
The small non-coding VTRNA1-1 (vault RNA 1-1) is known to confer resistance to apoptosis in several malignant cell lines and to also modulate the macroautophagic/autophagic flux in hepatocytes, thus highlighting its pro-survival role. Here we describe a new function of VTRNA1-1 in regulating in vitro and in vivo tumor cell proliferation, tumorigenesis and chemoresistance. Knockout (KO) of VTRNA1-1 in human hepatocellular carcinoma cells reduced nuclear localization of TFEB (transcription factor EB), leading to a downregulation of the coordinated lysosomal expression and regulation (CLEAR) network genes and lysosomal compartment dysfunction. We demonstrate further that impaired lysosome function due to loss of VTRNA1-1 potentiates the anticancer effect of conventional chemotherapeutic drugs. Finally, loss of VTRNA1-1 reduced drug lysosomotropism allowing higher intracellular compound availability and thereby significantly reducing tumor cell proliferation in vitro and in vivo. These findings reveal a so far unknown role of VTRNA1-1 in the intracellular catabolic compartment and describe its contribution to lysosome-mediated chemotherapy resistance.
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