Abstract LB023: Thyroid hormone receptor signaling promotes antiandrogen resistance and bone metastasis in prostate cancer

Abstract

Abstract Background: Systemic factors from the tumor microenvironment (TME) promote prostate cancer (PCa) progression, metastasis, and drug resistance. Therefore, the identification of the systemic factors that can modulate the tumor cells and promote metastases will be critical to improve the efficacy of clinical treatment. Both mechanistic and functional studies revealed that acquisition of an open chromatin state on master regulators or cis-regulatory elements allow them to respond readily to microenvironment signals, thereby increasing cancer cell plasticity, tumorigenicity and malignant potential. Accordingly, analysis of open chromatin regions can help prioritize and identify risk of functionally noncoding variants. Given the power of open chromatin profiling on environmental risk prediction, we hypothesized that analysis of open chromatin regions may enable us to recognize functional trans-regulatory elements with their relevant systemic factors. Methods and Results: In human prostate cancer cells, AR blockage by enzalutamide can induces cell reprogramming, as well as transcriptional dysregulation of the heterochromatin compaction pathway. Hence, we proposed that the cells were undergoing chromatin decondensation followed by epigenetic reprogramming. To detect the genome-wide open chromatin changes in this process, we performed time course ATAC-seq and H3K27ac ChIP-seq experiments on LNCaP cells treated with enzalutamide over a 2 weeks period. Bioinformatic analysis was performed to identify the “open” enhancers and the transcriptional factors potentially bound to these enhancers. Integrated transcription factor binding motif analysis of metastatic castration-resistant prostate cancer (mCRPC) associated enhancer regions (GSE130408) and multiplexed siRNA screening revealed Thyroid Hormone Receptor Beta (THRB) as the top candidate. THRB is regulated by the thyroid hormone (T3), a systemic nuclear hormone that, in enzalutamide pretreated LNCaP, VCaP and 3PDXs, is able to induce subsequent reprogramming to a fully enzalutamide-resistant and metastatic state. Interestingly, we observed that THRB regulated genes are upregulated in T3-induced resistant prostate cancer cells. Consistently, the THRB protein, TRβ, is abundant in several aggressive PCa cell lines. Notably, knockdown of THRB reverted the growth and the bone metastatic potential of highly aggressive PCa models, such as Ptenpc-/-Smad4pc-/- and PC3M cells. Furthermore, both transcriptomic and functional analyses identified RUNX2 as a transcriptional target of THRB. In summary, we identify a novel mechanism of THRB-mediated tumor progression and drug resistance in PCa cells. Conclusion: Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. Accordingly, our results suggest a new mechanism for thyroid hormone signaling regulating metastasis potential and drug resistance. This study will provide a new perspective to identify the signals from the TME that may increase the risk of PCa progression. Citation Format: Yan Wang, Gurrapu Harsha, Dhiraj Kumar, Josue Curto, Xiaobo Wang, Filippo Giancotti. Thyroid hormone receptor signaling promotes antiandrogen resistance and bone metastasis in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB023.