Genome-wide CRISPR screen identifies splicing factor SF3B4 in driving hepatocellular carcinoma.

Although genome sequencings have recognized many cancer-associated genes in hepatocellular carcinoma (HCC), distinguishing their functional effect remains challenging. Leveraging on a genome-wide CRISPR knockout (KO) screening, we uncovered spliceosome factors as major survival essential genes in HCC and up-regulations of ferroptosis suppressors [particularly glutamate-cysteine ligase catalytic subunit (GCLC)] in lenvatinib ...
resistance. Our KO screen in patient-derived HCC organoid showed splicing factor 3b subunit 4 (SF3B4) to be top-ranked, conferring prosurvival signal in HCC organoid and driving tumorigenic potentials in both hepatic progenitor organoids and hydrodynamic tail vein injection HCC murine model. The combined RNA immunoprecipitation sequencing, long-read isoform sequencing, and transcriptome revealed characteristic splicing landscape regulated by SF3B4 and identified T-box transcription factor 3 (TBX3) variant TBX3+2a as a potent downstream effector. Our findings highlighted vital roles of SF3B4 in HCC cell survival and tumor progression, and the phenomenon of ferroptosis resistance in patients unresponsive to first-line agent lenvatinib.
Mesh Terms:
Animals, CRISPR-Cas Systems, Carcinoma, Hepatocellular, Cell Line, Tumor, Clustered Regularly Interspaced Short Palindromic Repeats, Drug Resistance, Neoplasm, Ferroptosis, Gene Expression Regulation, Neoplastic, Humans, Liver Neoplasms, Mice, Phenylurea Compounds, Quinolines, RNA Splicing Factors, T-Box Domain Proteins
Sci Adv
Date: Oct. 10, 2025
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