The Polacek lab (DCBP, University of Bern) together with the Candinas group (DBMR, Insel Hospital, University of Bern) gained insights into how human vault RNA 1-1 contributes to tumorigenesis and chemoresistance in hepatocellular carcinoma and their findings point at vault RNA 1-1 as a possible target for battling cancers employing this mechanism. Their findings were published in the Autophagy journal in an article entitled "The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome in hepatocellular carcinoma".
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.