# Pan‐cancer multi‐omics reveals DCAF7 as an immune‐modulating prognostic driver and Wnt/β‐catenin activator in hepatocellular carcinoma

## TL;DR

DCAF7 is a cancer-related protein linked to poor prognosis in liver cancer and immune evasion, with potential as a treatment target.

## Contribution

The study identifies DCAF7 as a pan-cancer immune-modulating driver and Wnt/β-catenin activator in hepatocellular carcinoma.

## Key findings

- DCAF7 overexpression correlates with poor prognosis in hepatocellular carcinoma (LIHC).
- High DCAF7 expression is associated with immune checkpoint gene upregulation and tumor immune escape.
- DCAF7 promotes cancer cell proliferation via Wnt/β-catenin signaling and is a potential therapeutic target.

## Abstract

DDB1 and CUL4‐associated factor 7 (DCAF7) is a WD‐repeat adaptor that recruits substrates to the CUL4DDB1 ubiquitinligase complex, but its pan‐cancer relevance and mechanistic contribution to tumor progression remain unclear.

Multi‐omics datasets (genomic, transcriptomic, epigenomic, proteomic and single‐cell) from 33 tumor types were integrated to define DCAF7 expression, regulation, and clinical significance. Somatic alterations and copy‐number variation were analysed across cohorts, and promoter methylation and RNA modification signatures were interrogated. Immune associations were assessed by computational deconvolution and checkpoint‐gene profiling. Pathway and network analyses were performed to infer DCAF7‐linked programmes. Mechanistic and functional validation was conducted in hepatocellular carcinoma (LIHC) cell lines (HepG2, Huh7) using DCAF7 perturbation and pharmacologic Wnt inhibition.

DCAF7 was overexpressed in most cancers, consistent with copy‐number gain, focal promoter hypomethylation and putative m6A‐linked post‐transcriptional regulation, whereas hypermethylation at two CpG loci predicted poor prognosis in LIHC. DCAF7 alterations, predominantly amplifications, were associated with shorter overall survival in LIHC and positively correlated with DCAF7 mRNA abundance across cohorts. Immunogenomic analyses linked high DCAF7 to CD4+ T‐cell enrichment, broad upregulation of checkpoint genes (PD‐1/PD‐L1, CTLA‐4, TIGIT), and increased tumour mutational burden, microsatellite instability and neoantigen load, suggesting an immune‐evasive phenotype. Network and enrichment analyses converged on canonical Wnt/β‐catenin, Hippo and cell‐cycle programs. In vitro, DCAF7 promoted LIHC cell proliferation and migration by stabilising β‐catenin via increased inhibitory Ser9 phosphorylation of GSK‐3β, thereby inducing c‐Myc and cyclin D1; DCAF7 knockdown or the Wnt inhibitor XAV939 attenuated these effects. Drug‐response modelling further predicted increased sensitivity of DCAF7‐high tumours to 17‐AAG, docetaxel and alsterpaullone.

DCAF7 is frequently activated by genetic and epigenetic mechanisms across cancers, associates with an immunotherapy‐relevant tumour immune milieu, and drives Wnt/β‐catenindependent malignant phenotypes in LIHC. These findings support DCAF7 as a prognostic biomarker and a candidate therapeutic target, particularly for stratified intervention in LIHC.

DCAF7 is up‐regulated in various tumours and correlates with poor prognosis, particularly in LIHC.High DCAF7 expression is linked to CD4+ T cell infiltration, up‐regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape.DCAF7 stabilises β‐catenin by enhancing GSK‐3β Ser9 phosphorylation, thereby driving c‐Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC.DCAF7‐high tumours demonstrate therapeutic vulnerability to 17‐AAG, docetaxel and CDK/GSK‐3 inhibitor, revealing potential targeted treatment strategies.

DCAF7 is up‐regulated in various tumours and correlates with poor prognosis, particularly in LIHC.

High DCAF7 expression is linked to CD4+ T cell infiltration, up‐regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape.

DCAF7 stabilises β‐catenin by enhancing GSK‐3β Ser9 phosphorylation, thereby driving c‐Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC.

DCAF7‐high tumours demonstrate therapeutic vulnerability to 17‐AAG, docetaxel and CDK/GSK‐3 inhibitor, revealing potential targeted treatment strategies.

DCAF7 is up‐regulated in various tumours and correlates with poor prognosis, particularly in LIHC.High DCAF7 expression is linked to CD4+ T cell infiltration, up‐regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape.DCAF7 stabilises β‐catenin by enhancing GSK‐3β Ser9 phosphorylation, thereby driving c‐Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC.DCAF7‐high tumours demonstrate therapeutic vulnerability to 17‐AAG, docetaxel and CDK/GSK‐3 inhibitor, revealing potential targeted treatment strategies.

DCAF7 is up‐regulated in various tumours and correlates with poor prognosis, particularly in LIHC.

High DCAF7 expression is linked to CD4+ T cell infiltration, up‐regulation of immune checkpoint genes and increased tumour mutational burden, suggesting a role in tumour immune escape.

DCAF7 stabilises β‐catenin by enhancing GSK‐3β Ser9 phosphorylation, thereby driving c‐Myc/cyclin D1 expression and contributing to proliferation and migration in LIHC.

DCAF7‐high tumours demonstrate therapeutic vulnerability to 17‐AAG, docetaxel and CDK/GSK‐3 inhibitor, revealing potential targeted treatment strategies.