Distinct Transcriptional Programs Controlled by NR5A1 and β-Catenin in Adrenocortical Carcinoma

Background/Objectives: Adrenocortical carcinoma (ACC) is a rare malignancy in which overexpression of steroidogenic factor-1 (SF-1/NR5A1) and aberrant activation of canonical Wnt/β-catenin signaling are important oncogenic events. However, the extent to which these regulatory axes converge or interact at the transcriptional level remains unclear. We investigated their relationship using bulk transcriptomic and regulatory-network approaches. Methods: Regulatory network inference using RTN/ARACNe was applied to the TCGA-ACC cohort. NR5A1 and β-catenin-associated TCF/LEF regulon activities were evaluated in perturbation datasets and tested for associations with CpG island methylator phenotype (CIMP), overall survival, and gene-level interaction effects. Candidate modulators of NR5A1 activity were assessed using the MINDy algorithm. The effects of cBAF inhibition on NR5A1 regulon activity were also evaluated in H295R and CU-ACC1 cells. Results: NR5A1 knockdown repressed steroidogenic pathways, whereas β-catenin knockdown predominantly suppressed Wnt/β-catenin signaling. In TCGA-ACC, NR5A1 regulon activity was associated with CIMP-high status and overall survival. In contrast, β-catenin-related regulons were not significantly associated with CIMP-high status after adjustment for NR5A1 activity, and no significant multiplicative interaction effects were identified. Fewer than 3% of protein-coding genes showed improved fit in models including NR5A1 × TCF/LEF interaction terms, without enrichment for steroidogenic or Wnt/β-catenin-related pathways. CTNNB1 was identified as a statistically significant but low-ranking positive modulator of NR5A1 activity, whereas CTNNBIP1 was a top-decile negative modulator. cBAF inhibition was associated with NR5A1 regulon repression in both cell models. Conclusions: These findings indicate limited detectable global transcriptional convergence between NR5A1 and canonical β-catenin-related regulons in the evaluated bulk transcriptomic frameworks. Potential relationships between these pathways may depend on more localized, chromatin-dependent, protein-level, or context-specific regulatory mechanisms. NR5A1 regulon activity showed more consistent associations with CIMP-high status and clinical outcome than the β-catenin/TCF-LEF regulons in the evaluated TCGA-ACC models. The modulation patterns associated with CTNNB1 and CTNNBIP1, together with the repression of NR5A1 regulon activity following cBAF inhibition, raise the possibility that NR5A1 acts as a context-dependent regulatory node connecting oncogenic signaling and chromatin-remodeling mechanisms in ACC. These findings support further investigation into the role of chromatin-remodeling complexes in sustaining NR5A1-driven transcriptional programs in ACC.