Enzalutamide-induced signatures revealed by epigenetic plasticity using single-cell multi-omics sequencing in prostate cancer

Huihui Fan; Jinze Li; Astrid M Manuel; Zhongming Zhao

doi:10.1016/j.omtn.2023.02.022

Enzalutamide-induced signatures revealed by epigenetic plasticity using single-cell multi-omics sequencing in prostate cancer

Mol Ther Nucleic Acids. 2023 Feb 18:31:648-661. doi: 10.1016/j.omtn.2023.02.022. eCollection 2023 Mar 14.

Authors

Huihui Fan^{1

2}, Jinze Li³, Astrid M Manuel¹, Zhongming Zhao^{1

4

5}

Affiliations

¹ Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
² Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
³ Environmental and Occupational Health Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁴ Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
⁵ MD Anderson Cancer Center, University of Texas Health Graduate School of Biomedical Sciences, Houston, TX 77030, USA.

Abstract

Prostate cancer is morphologically and molecularly heterogeneous, which poses obstacles for early diagnosis and treatment. Advancements in understanding the heterogeneity of prostate cancer will help navigate through these challenges and ultimately benefit patients. In this study, we integrated single-cell sequencing for transposase-accessible chromatin and whole transcriptome in prostate cancer cell lines, aiming to decode the epigenetic plasticity upon enzalutamide (ENZ) treatment. By comparing the cell populations representing early-treatment response or resistance to the initial tumor cells, we identified seven signature gene sets; they present consistent trends of chromatin closing co-occurred with down-regulated genes during early response and chromatin opening with up-regulated genes upon maintaining drug resistance. In the molecular signatures, we found genes ZNF337, MAPK15, and ESRRG are favorable in progression-free prognosis during early response, while genes CCDC150, CCDC18, and POC1A marked poor prognosis underpinning the pre-existing drug resistance in The Cancer Genome Atlas prostate adenocarcinoma cohort. Ultimately, drug-target analyses nominated combinatory drug candidates to either enhance early-treatment response or potentially overcome ENZ resistance. Together, our integrative, single-cell multi-omics approach in pre-clinical models is effective in identifying informative signatures from complex molecular events, illustrating diverse drug responses in prostate cancer, and invoking novel combinatory drug strategies to inform clinical decision making.

Keywords: MT: Bioinformatics; combinatory drug candidates; enzalutamide treatment; prostate cancer; single-cell ATAC sequencing; single-cell RNA sequencing; tumor prognosis.