The GSEC-encoded polypeptide GESP drives colorectal cancer tumorigenesis via NPM1-c-Myc-mediated repression of NDRG1.

Expression of long non-coding RNAs (lncRNAs) is frequently dysregulated in human cancers. We previously reported that the lncRNA GSEC accelerates colorectal cancer (CRC) cell motility by inhibiting the RNA helicase DHX36. Here, we demonstrated that a nuclear polypeptide (designated 'GESP') is translated from a short ORF encoded by GSEC, which is highly expressed in CRC cells. In vivo experiments using CRC cell-xenografted mice revealed that GESP is required for development of immature tumors through suppression of a critical differentiation factor, NDRG1. Suppression of GESP by shRNA-mediated knockdown of GSEC caused growth retardation associated with tumor differentiation. At the molecular level, GESP recruits c-Myc to the promoter region of NDRG1 by forming a GESP-NPM1-c-Myc complex, which consequently represses transcription of NDRG1. Collectively, these data indicate a novel lncRNA product, GESP, plays a pivotal role in CRC tumor development/progression by suppression of tumor cell differentiation through the GESP-NDRG1 axis.