EGF-Upregulated lncRNA ESSENCE Promotes Colorectal Cancer Growth through Stabilizing CAD and Ferroptosis Defense

Epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signaling is highly activated in various types of cancer. The long noncoding RNAs induced by this pathway and their roles in colorectal cancer (CRC) have not been fully elucidated. In this study, based on the profiling of long noncoding RNAs triggered by EGFR/MAPK signaling, we identified that ESSENCE (EGF [epidermal growth factor] Signal Sensing CAD's Effect; ENST00000415336), which is mediated by the transcription factor early growth response factor 1, functions as a potent oncogenic molecule that predicts poor prognosis in CRC. Mechanistically, ESSENCE directly interacts with carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) and competitively attenuates CAD degradation mediated by its newly discovered E3 ligase KEAP1, thereby suppressing ferroptosis and promoting CRC progression. Importantly, combinational treatment of the mitogen-activated extracellular signal-regulated kinase inhibitor selumetinib and ferroptosis inducer sulfasalazine synergistically suppresses ESSENCE-high CRC in a patient-derived xenograft mouse model. Taken together, these findings demonstrate the crucial role of ESSENCE in mediating CRC progression by regulating CAD stabilization and suggest a therapeutic strategy of targeting the ESSENCE-CAD axis in CRC.