The human vault RNA enhances tumorigenesis and chemoresistance through the lysosome

Abstract

The small non-coding vault RNA (vtRNA) 1-1 has been shown to confer apoptosis resistance in several malignant cell lines and also to modulate the 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. By activating extracellular signal-regulated kinases (ERK 1/2), vtRNA1-1 knock-out (KO) inhibits transcription factor EB (TFEB), leading to a downregulation of the coordinated lysosomal expression and regulation (CLEAR) network genes and lysosomal compartment dysfunction. Pro-tumorigenic pathways dysregulation and decreased lysosome functionality potentiate the anticancer effect of conventional targeted cancer drugs in the absence of vtRNA1-1. Finally, vtRNA1-1 KO-reduced lysosomotropism, together with a higher intracellular compound availability, significantly reduced tumor cell proliferation in vitro and in vivo. These findings reveal the role of vtRNA1-1 in ensuring intracellular catabolic compartment stability and functionality, suggesting its importance in lysosome-mediated chemotherapy resistance.

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

“… Vault RNAs are abundantly expressed in liver samples. Northern blot analysis in paired patient-derived tissues was performed as described in [ 53 ] and revealed that vtRNA1-1 and vtRNA1-2 are expressed in metastatic but not in non-pathological adjacent liver tissues; healthy (H), tumor (T) and metastasis (M). 5.8S rRNA serves as internal loading control.…”

“…This regulation of exosomes carried out by MVP indirectly affects the efficacy of chemotherapy treatment and the tumor progression of colon cancer. MVP has also been reported to contribute to temozolomide (TMZ)-resistance in glioblastoma [ 53 ]. The expression of MVP increased in glioblastoma with TMZ resistance, and its sensitivity to the drug was inhibited by increased MVP.…”