RPSAP52 lncRNA inhibits p21Waf1/CIP expression by interacting with the RNA binding protein HuR

Long-non coding RNAs have been recently demonstrated to have an important role in fundamental biological processes, and their deregulated expression has been found in several human neoplasias. Our group has recently reported a drastic overexpression of the lncRNA RPSAP52 in pituitary adenomas. We have shown that this lncRNA increased cell proliferation by upregulating the expression of the chromatinic proteins HMGA1 and HMGA2, functioning as a ceRNA through competitively binding to miR-15a, miR-15b and miR-16. The aim of this work has been to identify further mechanisms by which RPSAP52 overexpression could contribute to the development of pituitary adenomas. We investigated the involvement of RPSAP52 in the modulation of the expression of cell cycle-related genes, such as p21Waf1/Cip, whose deregulation plays a critical role in pituitary cell transformation. We report that RPSAP52, interacting with the RNA binding protein HuR, favors the delocalization of miR-15a, miR-15b and miR-16on the cyclin45 dependent kinase inhibitor p21Waf1/Cip1 that, accordingly, results downregulated in pituitary adenomas. A RIPseq analysis performed on cells overexpressing RPSAP52 identified 40 mRNAs enriched in AGO2 immunoprecipitated samples. Among them we focused on GAS8 (Growth Arrest-Specific Protein 8) gene. Consistently, GAS8 expression was downregulated in all the analyzed pituitary adenomas with respect to normal pituitary and in RPSAP52-overepressing cells, supporting the role of RPSAP52 in addressing genes involved in growth inhibition and cell cycle arrest to miRNA-induced degradation. This study unveils another RPSAP52-mediated molecular mechanism in pituitary tumorigenesis.