The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome in hepatocellular carcinoma

Iolanda Ferro; Jacopo Gavini; Stefano Gallo; Lisamaria Bracher; Marc Landolfo; Daniel Candinas; Deborah M Stroka; Norbert Polacek

doi:10.1080/15548627.2021.1922983

The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome in hepatocellular carcinoma

Autophagy. 2022 Jan;18(1):191-203. doi: 10.1080/15548627.2021.1922983. Epub 2021 May 7.

Authors

Iolanda Ferro¹, Jacopo Gavini², Stefano Gallo^{1

3}, Lisamaria Bracher^{1

3}, Marc Landolfo¹, Daniel Candinas², Deborah M Stroka², Norbert Polacek¹

Affiliations

¹ Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
² Department of Visceral Surgery and Medicine, Department for BioMedical Research, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
³ Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

Abstract

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.Abbreviations: ATP6V0D2: ATPase H+ transporting V0 subunit d2; BafA: bafilomycin A1; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; DMSO: dimethyl sulfoxide; GST-BHMT: glutathionine S-transferase N-terminal to betaine-homocysteine S-methyltransferase; HCC: hepatocellular carcinoma; LAMP1: lysosomal associated membrane protein 1; LLOMe: L-leucyl-L-leucine methyl ester; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAPK: mitogen-activated protein kinase; MITF: melanocyte inducing transcription factor; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ncRNA: non-coding RNA; RNP: ribonucleoprotein; SF: sorafenib; SQSTM1/p62: sequestosome 1; STS: staurosporine; tdRs: tRNA-derived RNAs; TFE3: transcription factor binding to IGHM enhancer 3; TFEB: transcription factor EB; vtRNA: vault RNA transcript.

Keywords: Chemoresistance; lysosome; non-coding RNA; tumorigenesis; vault RNA; vtRNA1-1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autophagy
Carcinogenesis / genetics
Carcinogenesis / metabolism
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Carcinoma, Hepatocellular* / metabolism
Drug Resistance, Neoplasm / genetics
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Liver Neoplasms* / metabolism
Lysosomes / metabolism
RNA / metabolism

Substances

RNA

Grants and funding

The work was primarily supported by the NCCR “RNA & Disease” funded by the Swiss National Science Foundation [18280 to N.P.] Additional support from the Ruth and Arthur Scherbarth Foundation (to N.P.) and by the Aclon Foundation (to D.S.) is acknowledged;NCCR RNA & Disease [18280].