Browsing by Author "Chen, Xufeng"

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    Protein arginine methyltransferase 5 promotes pICln-dependent androgen receptor transcription in castration-resistant prostate cancer
    (American Association for Cancer Research, 2020-11-15) Beketova, Elena; Fang, Shuyi; Owens, Jake L.; Liu, Sheng; Chen, Xufeng; Zhang, Qingfu; Asberry, Andrew M.; Deng, Xuehong; Malola, Jonathan; Huang, Jiaoti; Li, Chenglong; Pili, Roberto; Elzey, Bennett D.; Ratliff, Timothy L.; Wan, Jun; Hu, Chang-Deng; BioHealth Informatics, School of Informatics and Computing
    The majority of advanced prostate cancer therapies aim to inhibit androgen receptor (AR) signaling. However, AR reactivation inevitably drives disease progression to castration-resistant prostate cancer (CRPC). Here we demonstrate that protein arginine methyltransferase 5 (PRMT5) functions as an epigenetic activator of AR transcription in CRPC, requiring cooperation with a methylosome subunit pICln. In vitro and in xenograft tumors in mice, targeting PRMT5 or pICln suppressed growth of CRPC cells. Full-length AR and AR-V7 transcription activation required both PRMT5 and pICln but not MEP50. This activation of transcription was accompanied by PRMT5-mediated symmetric dimethylation of H4R3 at the proximal AR promoter. Further, knockdown of PRMT5 abolished the binding of pICln (but not vice versa) to the AR proximal promoter region, suggesting that PRMT5 recruits pICln to the AR promoter to activate AR transcription. Differential gene expression analysis in 22Rv1 cells confirmed that PRMT5 and pICln both regulate the androgen signaling pathway. In addition, PRMT5 and pICln protein expression positively correlated with AR and AR-V7 protein expression in CRPC tissues and their expression was highly correlated at the mRNA level across multiple publicly available CRPC datasets. Our results suggest that targeting PRMT5 or pICln may be explored as a novel therapy for CRPC treatment by suppressing expression of AR and AR splice variants to circumvent AR reactivation. SIGNIFICANCE: This study provides evidence that targeting PRMT5 can eliminate expression of AR and can be explored as a novel therapeutic approach to treat metastatic hormone-naïve and castration-resistant prostate cancer.
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    Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion
    (Elsevier, 2023) Battistello, Elena; Hixon, Kimberlee A.; Comstock, Dawn E.; Collings, Clayton K.; Chen, Xufeng; Rodriguez Hernaez, Javier; Lee, Soobeom; Cervantes, Kasey S.; Hinkley, Madeline M.; Ntatsoulis, Konstantinos; Cesarano, Annamaria; Hockemeyer, Kathryn; Haining, W. Nicholas; Witkowski, Matthew T.; Qi, Jun; Tsirigos, Aristotelis; Perna, Fabiana; Aifantis, Iannis; Kadoch, Cigall; Medicine, School of Medicine
    Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.