β-Catenin–Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer

Abstract

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent β-catenin activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific β-catenin-containing complexes and the epigenome. On chromatin, β-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, β-catenin bound histone methyltransferase EZH2. SF1/β-catenin and EZH2/β-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/β-catenin from chromatin and favored EZH2/β-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

A reappraisal of transcriptional regulation by NR5A1 and beta-catenin in adrenocortical carcinoma

“…Overall, in contrast to the conclusions by the Mohan et al. article ( 17 ), these data provide compelling evidence that in ACC cells NR5A1 and beta-catenin, which are both relevant factors driving tumour malignancy, regulate mostly distinct gene expression programs through different mechanisms. We have demonstrated that NR5A1 overexpression in ACC cells regulates the expression of both positive and negative dosage-dependent target genes which are directly implicated in shaping the malignant tumour phenotype ( 3 – 8 ).…”

“…My analysis performed using MACS2 software on the ChIP-seq data from the Mohan et al.’s study ( 17 ) revealed a total of 47,071 genomic binding sites for NR5A1 and 1,055 binding sites for beta-catenin within H295R cells. Notably, there were 979 binding sites overlapping binding sites ( Figure 1A , Supplementary Table S1 for details).…”

“…However, the study by Mohan et al. ( 17 ) has been the first to investigate the localization of both NR5A1 and beta-catenin binding sites in the chromatin of H295R ACC cells at the genome-wide scale. Those authors concluded that the interaction between those factors is a major determinant driving proliferation and differentiation in malignant ACC.…”

“…NR5A1 (basal; SRR19503712), beta-catenin (basal; SRR19503710) ChIP-seq and input DNA (SRR19503702) fastq files from the study by Mohan et al. ( 17 ) were retrieved from the SRA database ( https://www.ncbi.nlm.nih.gov/sra ). All data analyses were performed in the Galaxy server ( https://usegalaxy.eu ) ( 18 ).…”

“…Little is known about the potential interplay of those factors in driving ACC malignancy. Based on the analysis of genomic profiles in H295R cells, a recent study suggested that a major determinant driving proliferation and differentiation in malignant ACC is the interaction of NR5A1 and beta-catenin on chromatin to regulate gene expression ( 17 ). However, by the analysis of the data generated by Mohan et al.…”