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

SIMPLE SUMMARY: Small non-protein-coding RNAs have been recognized as valuable regulators of gene expression in all three domains of life. Particularly in multicellular organisms, ncRNAs-mediated gene expression control has evolved as a central principle of cellular homeostasis. Thus, it is not surprising that non-coding RNA misregulation has been linked to various diseases. Here, we review the contributions of the four human vault RNAs to cellular proliferation, apoptosis and cancer biology. ABSTRACT: The importance of non-coding RNAs for regulating gene expression has been uncovered in model systems spanning all three domains of life. More recently, their involvement in modulating signal transduction, cell proliferation, tumorigenesis and cancer progression has also made them promising tools and targets for oncotherapy. Recent studies revealed a class of highly conserved small ncRNAs, namely vault RNAs, as regulators of several cellular homeostasis mechanisms. The human genome encodes four vault RNA paralogs that share significant sequence and structural similarities, yet they seem to possess distinct roles in mammalian cells. The alteration of vault RNA expression levels has frequently been observed in cancer tissues, thus hinting at a putative role in orchestrating pro-survival characteristics. Over the last decade, significant advances have been achieved in clarifying the relationship between vault RNA and cellular mechanisms involved in cancer development. It became increasingly clear that vault RNAs are involved in controlling apoptosis, lysosome biogenesis and function, as well as autophagy in several malignant cell lines, most likely by modulating signaling pathways (e.g., the pro-survival MAPK cascade). In this review, we discuss the identified and known functions of the human vault RNAs in the context of cell proliferation, tumorigenesis and chemotherapy resistance.