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

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.

Small but Powerful: The Human Vault RNAs as Multifaceted Modulators of Pro-Survival Characteristics and Tumorigenesis

“…In HeLa cells, which derive from cervical adenocarcinoma, the knock out (KO) of the vtRNA1-1 lead to a significant decrease in cell proliferation [ 48 ]. The proliferation defect following a vtRNA1-1 KO was also observed in the hepatocellular carcinoma cell line Huh-7 [ 49 ]. In both KO cell lines, vtRNA1-1 was re-introduced in the genome by lentiviral transduction, and these vtRNA1-1 complemented cell lines rescued the growth defect [ 48 , 49 ].…”

“…The proliferation defect following a vtRNA1-1 KO was also observed in the hepatocellular carcinoma cell line Huh-7 [ 49 ]. In both KO cell lines, vtRNA1-1 was re-introduced in the genome by lentiviral transduction, and these vtRNA1-1 complemented cell lines rescued the growth defect [ 48 , 49 ]. These studies revealed that, in cancer cells, vtRNA1-1 is an important proliferation factor and its absence impairs cell growth.…”

“…What is critically important is that the re-expression of the vault RNA1-1 rescued the resistance to apoptosis. Interestingly, hepatocellular carcinoma line Huh-7 is the sole cancer cell line investigated so far for which its apoptotic behavior is not regulated by vtRNA1-1 levels [ 49 ]. This mechanism of cell survival is stimulated upon vtRNA1-1 expression via the activation of PI3K/AKT (phosphoinositide-3-kinase–protein kinase B/Akt) and ERK1/2 MAPK (extracellular signal-regulated kinase 1/2 and mitogen-activated protein kinase) signaling pathways [ 48 ].…”

“…Cumulatively, the available evidence demonstrates that, with the exception of hepatocellular carcinoma [ 49 ], vtRNA1-1 plays a pivotal role in apoptosis resistance in several human cancer cell lines.…”

“…A more recent study provided a somewhat different and maybe more comprehensive perspective on the link between vtRNA1-1 and autophagy. In the hepatocellular carcinoma cell line Huh-7, the deletion of vtRNA1-1, or its reduction upon starvation, stimulated the ERK1/2-MAPK signaling pathway [ 49 ]. As a consequence, the phosphorylation of the transcription factor EB (TFEB), which is the master regulator of lysosomal biogenesis genes [ 49 , 66 , 67 ], becomes hyper-phosphorylated.…”