Brinkman, J. | Search bioRxiv

bioRxiv2026

Loss of cBAF Complex Confers Sorafenib Resistance in Liver Cancer

Sorafenib resistance limits the clinical benefit of first-line therapy in hepatocellular carcinoma (HCC), yet the epigenetic mechanisms underlying this resistance remain poorly understood. Using a chromatin-focused CRISPR/Cas9 dropout screen in HepG2 cells, we identified subunits of the canonical BAF (cBAF) complex -- ARID1A, ARID1B, and SMARCC1 -- as functional drivers of sorafenib resistance, while loss of the PBAF-specific subunit ARID2 had no effect, implicating cBAF specifically rather than SWI/SNF broadly. ARID1A and ARID1B mutations are associated with significantly worse overall survival in TCGA hepatocellular carcinoma cohorts. To define the underlying mechanism, we performed CUT&RUN profiling and RNA-seq in ARID1B-knockout HepG2 cells under sorafenib treatment. ARID1B loss triggered selective depletion of H3K4me3 and H3K27ac at 74 cBAF-dependent regulatory elements, 72% of which were directly occupied by ARID1B in wild-type cells. These sites were enriched for FOXA1 and HNF4 motifs, consistent with disruption of hepatocyte lineage regulatory chromatin. Direct profiling in HLF hepatocellular carcinoma cells confirmed that 179 FOXA1 binding sites were lost specifically under the combined perturbation of ARID1B loss and sorafenib treatment, with neither condition alone sufficient to drive this effect. Transcriptionally, ARID1B loss induced epithelial-mesenchymal transition programs and suppressed MYC targets, E2F targets, and mTORC1 signaling. These findings define a cBAF-FOXA1 regulatory axis that maintains hepatocyte lineage identity under kinase inhibitor stress, and whose disruption drives epigenetic reprogramming toward a mesenchymal drug-tolerant state. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/731725v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1ce2352org.highwire.dtl.DTLVardef@70f2f5org.highwire.dtl.DTLVardef@15ee96borg.highwire.dtl.DTLVardef@2e7edd_HPS_FORMAT_FIGEXP M_FIG C_FIG

Cancer Biology↗

bioRxiv2024

Mutant IDH uncouples p53 from target gene regulation to disable tumor suppression

p53 prevents tumor initiation and progression via transcriptional regulation of target gene networks. Here, we find that cancer-associated mutations in isocitrate dehydrogenase (IDH) can uncouple p53 activity from tumor suppression by perturbing chromatin states that determine target gene expression. Mutant IDH impairs tumor regressions and promotes the outgrowth of cancer cells with transcriptionally active, wild-type p53 in a mouse model of liver cancer where restoration of p53 activity results in tumor clearance. Mutant IDH alters p53 target gene expression through the oncometabolite 2-hydroxyglutarate (2-HG), an inhibitor of alpha-ketoglutarate (KG)-dependent chromatin remodeling enzymes, without preventing p53 accumulation or global genomic binding. Rather, mutant IDH alters chromatin accessibility landscapes that dictate target gene expression, resulting in disabled upregulation of targets that execute tumor suppression. Specifically, mutant IDH disrupts the expression of pro-apoptotic p53 targets that enable p53-dependent tumor regressions, including the death ligand receptor Fas. Pharmacological inhibition of mutant IDH in TP53 wild-type cholangiocarcinoma cells, a tumor type where p53 and IDH mutations are mutually exclusive, potentiates p53 target gene expression and sensitizes cells to Fas ligand and chemotherapy-induced apoptosis. Therefore, we implicate the disruption of p53 target gene regulation as a reversible, oncogenic feature of cancer-associated IDH mutations. SIGNIFICANCEWe find that chromatin states altered by cancer-associated IDH mutations intersect with transcriptional regulation of p53 target genes. This reversible interaction may represent a strategy to reinvigorate latent tumor suppression in IDH mutant, p53 wild-type tumors.

cancer biology↗