Regulatory Role of Small Nucleolar RNAs in Human Diseases

Stepanov, Grigory A.; Filippova, Julia A.; Komissarov, Andrey B.; Kuligina, Elena V.; Richter, Vladimir A.; Semenov, Dmitry V.

Mammalian Cells. Specific increase in the expression level of several box C/D RNAs was detected in murine and human breast cancer cells [39] . Both breast cancer primary cultures and breast cancer cell lines (MCF-7 and ZR-75-1) exhibited increased level of U22, U3, U8, U94, and U97 box C/D snoRNAs compared to normal and untransformed (MCF-10A) human cells. Change in snoRNA expression level is accompanied by an increase in fibrillarin, the core component of snoRNPs, with its level correlating with the expression of Myc oncogene. High level of fibrillarin was observed not only in breast cancer cells, but also in prostate and many other human cancers. Targeted repression of fibrillarin and other proteins of the methyltransferase complex (NOP56 and NOP58) not only led to the decrease in box C/D snoRNA level, but also inhibited cancer cell growth and decreased oncogenicity [39] . siRNA-mediated knockdown of fibrillarin in cancer cells enhanced induction of tumor suppressor p53 protein. Meanwhile, increased fibrillarin expression resulted in significantly compromised p53-dependent response to stress in cancer cells. Earlier, it has been demonstrated that disrupted nucleolar activity, such as blocked transcription of rRNA genes, leads to p53 protein stabilization due to the binding between MDM2 (negative regulator of p53) and ribosomal proteins (RPL5, RPL11, and RPL23) [40] . Thus, the presented data elucidate the role of nucleolar components, including snoRNAs and snoRNP proteins, in survival of cancer cells by modulation of p53 expression.