Ferro, IolandaIolandaFerroGavini, JacopoJacopoGaviniGallo, StefanoStefanoGalloBracher, Lisa MariaLisa MariaBracherLandolfo, Marc PatrickMarc PatrickLandolfoCandinas, DanielDanielCandinasKeogh-Stroka, Deborah M.Deborah M.Keogh-Stroka0000-0002-3517-3871Polacek, NorbertNorbertPolacek0000-0001-5317-39902024-10-052024-10-052021-05-07https://boris-portal.unibe.ch/handle/20.500.12422/56815The 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.en600 - Technology::610 - Medicine & health500 - Science::570 - Life sciences; biology500 - Science::540 - Chemistryarticle10.48350/1562743396027010.1080/15548627.2021.1922983