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

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.