The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition

Abstract

Altres ajuts: We thank CERCA Program/Generalitat de Catalunya for their institutional support. This work was also supported by the Fundació La Marató de TV3, grant number #20131610 (S.G.), the AECC-Junta de Barcelona (S.G.), the Fundación Científica de la AECC under grant GCB13131578DEÁ (O.M.T.), the Health and Science Departments of the Catalan Government (Gen-eralitat de Catalunya). C.O.-M. is a pre-doctoral fellow funded by the Basque Government (PRE_2013_1_1009).One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52. RPSAP52 is abundantly present in the cytoplasm, where it interacts with the RNA binding protein IGF2BP2/IMP2, facilitating its binding to mRNA targets, promoting their translation by mediating their recruitment on polysomes and enhancing proliferative and self-renewal pathways. Notably, downregulation of RPSAP52 impairs the balance between the oncogene LIN28B and the tumor suppressor let-7 family of miRNAs, inhibits cellular proliferation and migration in vitro and slows down tumor growth in vivo. In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas. Overall, we reveal the roles of a transcribed pseudogene that may display properties of an oncofetal master regulator in human cancers