GSE167506
Targeted Escalation of Tyrosine Kinase Super-Enhancer Network Engineered by Acetylated HOXB13  Spurs Prostate Tumor Autonomy
While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) is unknown. Herein we report the lysine 13 (K13) acetylation of HOXB13 mediated by the histone acetyltransferase CBP/p300 regulates prostate tumor autonomy. The acK13-HOXB13 shadows H3K27ac at lineage specific SEs and surpasses it at CSEs. In contrast, mutation of  HOXB13 at K13  sensitizes CRPCs to Enzalutamide, disables spheroid and xenograft tumor formation. Mechanistically, the acK13-HOXB13 interacts with chromatin remodeling bromodomain proteins to regulate tumor-specific CSE selection.   These CSEs sprout at critical lineage genes NKX3-1, Androgen receptor (AR), AR regulator  ACK1 tyrosine kinase and tyrosine kinase ligands regulating angiogenesis. Single-cell transcriptomic analysis of human prostate tumor organoids reveal ACK1 expression underlies sensitivity to the small molecule  inhibitor (R)-9b over AR-targeted agents. Collectively, our studies reveal acK13-HOXB13 regulated epigenome as a key cog in prostate cancer cell autonomy. Overall design: Human prostate organoids were grown as described above. Single cell suspension was processed for library preparation as described in the 10X Genomics single cell suspension protocol. All samples were quantitated  twice on the bioanalyzer and checked to ensure integrity.  10x Single Cell/Nuclei RNAseq  Library and Sequencing Targeting 25K read pairs/cell.  The samples amplified well for adequate libraries set up as per the 10X Genomics protocol.  25k depth per cell  sequencing was performed  using the NovaSeq S4. The Cell Ranger software was used to align the reads to the reference genome. Cloupe browser analysis was performed to generate the t-SNE plot and UMAP clustering analysis.