Long noncoding RNA ESSENCE identified as key driver of colorectal cancer progression

Colorectal cancer (CRC) remains one of the most prevalent and deadly cancers worldwide, with rising incidence linked to dietary and lifestyle changes. Despite advances in surgery and chemotherapy, drug resistance and tumor recurrence pose marked challenges. The epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signaling pathway, frequently hyperactivated in CRC, drives tumor growth, but its downstream effectors-particularly noncoding RNAs-are not fully understood.

A research team from Sun Yat-sen University Sixth Affiliated Hospital has made a groundbreaking discovery in colorectal cancer (CRC) research, identifying a long noncoding RNA (lncRNA) named ESSENCE (EGF Signal Sensing CAD's Effect; ENST00000415336) as a critical regulator of tumor progression. The study reveals that ESSENCE stabilizes a key metabolic enzyme, CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), to promote cancer growth and suppress ferroptosis. The findings also propose a novel combination therapy targeting ESSENCE-high tumors, offering new hope for precision treatment.

ESSENCE: A new oncogenic player

Led by Dr. Xiangqi Meng and Dr. Mong-Hong Lee, the team identified ESSENCE as a top lncRNA upregulated by EGFR/MAPK signaling. ESSENCE expression correlates with poor prognosis in CRC patients and is transcriptionally activated by the EGF-induced transcription factor EGR1. Mechanistically, ESSENCE binds to CAD, a multifunctional enzyme critical for pyrimidine synthesis, and blocks its degradation by the E3 ligase KEAP1. This stabilization fuels cancer cell proliferation and ferroptosis defense.

Implications for precision medicine

To explore the potential of targeting the ESSENCE–CAD–ferroptosis axis in restraining CRC development, the research team established patient-derived xenograft (PDX) models. Combining the MEK inhibitor selumetinib and the ferroptosis inducer sulfasalazine synergistically suppressed tumor growth in ESSENCE-high PDX models, while ESSENCE-low tumors showed minimal response. These findings support the clinical potential of patient stratification based on ESSENCE expression levels to optimize combination therapy selection.

Future directions

The study demonstrates that ESSENCE serves not only as a prognostic biomarker but also as a directly targetable molecular driver in colorectal cancer. However, whether ESSENCE plays a similar oncogenic role in other malignancies beyond colorectal cancer remains to be explored. Additionally, the proposed combination therapy requires further preclinical validation before clinical translation.

Future study will focus on developing targeted therapies against the newly identified ESSENCE-CAD signaling axis, which may expand treatment strategies for a broader range of cancers. This study highlights the growing importance of lncRNAs in precision oncology and underscores the need for innovative approaches to combat treatment resistance.