Abstract B056: TBX10 is a super-enhancer–driven tumor suppressor defining a less aggressive subtype of prostate cancer

Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) represents a lethal stage of disease characterized by profound heterogeneity and limited therapeutic options. Super-Enhancers (SEs), large clusters of regulatory elements that drive high-level transcription of lineage-defining genes, play a central role in determining mCRPC progression. In this study, we identified TBX10 as a novel SE-driven transcription factor that is overexpressed in ∼15% of primary tumors (TCGA) and only ∼5% of mCRPC samples (SU2C). Notably, TBX10-positive CRPC tumors represent a less aggressive AR-dependent subtype, showing a lower frequency of PTEN, TP53, or RB1 loss and ETS fusions, as well as reduced cell cycle/proliferation signatures and decreased enrichment for distant metastases. However, the molecular function of TBX10 in prostate cancer has not been defined. Methods: TBX10 function was evaluated using RNAi–mediated knockdown in C4-2 cells and doxycycline-inducible TBX10 overexpression in 22Rv1 and C4-2 models. RNA-seq was performed to characterize transcriptional changes induced by TBX10 alteration, and ChIP-seq was used to define its chromatin-binding profile. Functional assays were conducted to assess effects on cell proliferation, migration, and metabolism. Results: RNA-seq analysis revealed that TBX10 suppresses oncogenic pathways, including glycolysis, AR signaling, and EMT, while activating tumor-suppressive programs such as the p53 pathway. Functional validation confirmed that TBX10 downregulates AR signaling and reduces the proliferation and migration of C4-2 cells. Metabolic profiling showed decreased glycolytic activity accompanied by increased intracellular free fatty acids, triglycerides, and free cholesterol levels. TBX10 also markedly suppresses PI3K/AKT pathway activation, further supporting its tumor-suppressive role. Conclusions: Our findings identify TBX10 as a novel SE-driven tumor-suppressive transcription factor that is only expressed in a less aggressive molecular subtype of prostate cancer. Loss of TBX10 enhances tumor aggressiveness and may correlate with worse clinical features and outcomes in CRPC. Overall, TBX10 may serve as a potential biomarker of favorable prognosis and a mechanistic link between super-enhancer regulation and prostate cancer progression. Citation Format: Nolan Patten, Songqi Zhang, Mingyu Liu, Jared Lourie, Kourosh Zarringhalam, Kai Zou, Jill Macoska, Changmeng Cai. TBX10 is a super-enhancer–driven tumor suppressor defining a less aggressive subtype of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nrB056.