Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring an urgent clinical need for novel predictive biomarkers and targeted therapies. While the canonical WNT/β-catenin pathway is known to frequently drive the c-MYC proto-oncogene in CRC, the precise promoter-proximal regulatory networks governing its expression have remained incompletely understood.

This new research, published in the Genes & Diseases journal by a collaborative scientific team primarily from Hangzhou Institute of Medicine, Chinese Academy of Sciences, Shanghai Jiao Tong University, and Fudan University, investigated the mechanistic role of a novel long non-coding RNA (lncRNA), AC004854.2, in reshaping c-MYC transcription and fueling CRC malignancy.

The study demonstrates that AC004854.2 is significantly upregulated in colorectal cancer tissues and is strongly associated with poor clinical outcomes. Elevated expression of AC004854.2 correlates with increased tumor aggressiveness and reduced overall survival across independent patient cohorts, highlighting its potential value as both a prognostic biomarker and therapeutic target.

Mechanistically, researchers uncovered a previously unrecognized molecular pathway through which AC004854.2 activates oncogenic signaling. AC004854.2 directly binds to the RNA-binding protein PUF60, competitively disrupting the inhibitory PUF60–FUBP1 complex that normally suppresses c-MYC transcription at the far-upstream element (FUSE) region of the c-MYC promoter. Disassembly of this repressor complex leads to enhanced c-MYC transcriptional activation, resulting in increased expression of downstream cell cycle regulators including CCND2 and CDK4.

Further investigation identified the transcription factor SOX4 as an upstream activator of AC004854.2. The study demonstrates that SOX4 directly binds the promoter region of AC004854.2 and enhances its transcription, establishing a SOX4–AC004854.2–c-MYC signaling axis that drives colorectal cancer progression. This finding integrates transcriptional regulation, RNA-mediated signaling, and oncogene activation into a unified mechanistic framework.

Functional experiments revealed that AC004854.2 exerts broad pro-tumorigenic effects in colorectal cancer cells. Overexpression of AC004854.2 significantly enhanced cellular proliferation, migration, invasion, and cell cycle progression, while silencing the lncRNA suppressed malignant behavior. In vivo studies further confirmed that AC004854.2 promotes tumor growth and progression in animal models.

Importantly, the oncogenic effects mediated by AC004854.2 were markedly attenuated by treatment with IZCZ-3, a selective c-MYC inhibitor, demonstrating that the tumor-promoting activity of AC004854.2 is highly dependent on c-MYC signaling. These findings provide strong preclinical evidence supporting therapeutic targeting of this pathway.

Collectively, this study identifies AC004854.2 as a central regulator of colorectal cancer progression through disruption of the PUF60–FUBP1 complex and activation of c-MYC transcription. By uncovering a novel lncRNA-driven oncogenic mechanism, the work highlights promising opportunities for biomarker development and targeted therapeutic intervention in colorectal cancer.

Reference
Title of Original Paper: SOX4-activated lncRNA AC004854.2 promotes colorectal cancer progression by disrupting the PUF60–FUBP1 complex and activating c-MYC transcription

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2026.102137

Funding Information:
The National Natural Science Foundation of China (No. 82473173, No. 82172925, No. 82272775, No. 82573146)
The Fujian Provincial Natural Science Foundation of China (No. 2024J011434, No. 2025J011501)

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