Xie Xiaoshan, Zhang Boyu, Peng Jingxuan, Ma Ning, Pan Qihao, Wei Yue, Jin Huilin, Yu Fenghai, Huang Xiaoling, Zhang Peng, Wang Jiarui, Zheng Jiaying, Ying Xiaofang, Liu Ran-Yi, Yu Hongyan, Lee Mong-Hong, Meng Xiangqi
Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Research (Wash D C). 2025 Apr 3;8:0649. doi: 10.34133/research.0649. eCollection 2025.
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.
表皮生长因子受体/丝裂原活化蛋白激酶（EGFR/MAPK）信号通路在多种类型的癌症中高度激活。该信号通路诱导产生的长链非编码RNA及其在结直肠癌（CRC）中的作用尚未完全阐明。在本研究中，基于对由EGFR/MAPK信号通路触发的长链非编码RNA的分析，我们鉴定出由转录因子早期生长反应因子1介导的ESSENCE（EGF[表皮生长因子]信号感知CAD的效应；ENST00000415336），它作为一种有效的致癌分子，可预测CRC患者的预后不良。从机制上讲，ESSENCE直接与氨甲酰磷酸合成酶2、天冬氨酸转氨甲酰酶和二氢乳清酸酶（CAD）相互作用，并竞争性减弱由其新发现的E3连接酶KEAP1介导的CAD降解，从而抑制铁死亡并促进CRC进展。重要的是，在患者来源的异种移植小鼠模型中，丝裂原活化的细胞外信号调节激酶抑制剂司美替尼和铁死亡诱导剂柳氮磺胺吡啶联合治疗可协同抑制ESSENCE高表达的CRC。综上所述，这些发现证明了ESSENCE在通过调节CAD稳定性介导CRC进展中的关键作用，并提出了靶向CRC中ESSENCE-CAD轴的治疗策略。
