2. Academic Validation
  3. EGF-Upregulated lncRNA ESSENCE Promotes Colorectal Cancer Growth through Stabilizing CAD and Ferroptosis Defense

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

  • Research (Wash D C). 2025 Apr 3:8:0649. doi: 10.34133/research.0649.
Xiaoshan Xie 1 2 3,  Boyu Zhang 1 2 3,  Jingxuan Peng 1 2 3,  Ning Ma 1 2 3,  Qihao Pan 2 3 4,  Yue Wei 1 2 3,  Huilin Jin 2 3 5,  Fenghai Yu 1 2 3,  Xiaoling Huang 1 2 3,  Peng Zhang 1 2 3,  Jiarui Wang 1 2 3,  Jiaying Zheng 1 2 3,  Xiaofang Ying 6,  Ran-Yi Liu 7,  Hongyan Yu 8,  Mong-Hong Lee 1 2 3,  Xiangqi Meng 1 2 3
Affiliations

Affiliations

  • 1 Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 2 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.
  • 3 Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 4 Department of Obstetrics and Gynecology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 5 Department of Hepatobiliary, Pancreatic and Splenic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
  • 6 Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China.
  • 7 State Key Laboratory of Oncology in South China & Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
  • 8 Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
PMID: 40190348 DOI: 10.34133/research.0649
Abstract

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.

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