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Theranostics 2021; 11(13):6526-6541. doi:10.7150/thno.53886 This issue Cite

Research Paper

Targeted inhibition of SIRT6 via engineered exosomes impairs tumorigenesis and metastasis in prostate cancer

Qing Han^1#, Qian Rueben Xie^1#, Fan Li¹, Yirui Cheng¹, Tingyu Wu¹, Yanshuang Zhang¹, Xin Lu¹, Alice S.T. Wong³, Jianjun Sha^2✉, Weiliang Xia^1✉

1. State Key Laboratory of Oncogenes and Related Genes, Ren Ji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
2. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3. School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong.
#These authors contributed equally to this work.

✉ Corresponding authors: Weiliang Xia, PhD, Med-X Research Institute, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China. Phone: +86-21-62933351; Mobil: +86-13585887951. E-mail: wlxiaedu.cn. Dr. Jianjun Sha, Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle road, 200001, Shanghai, China; Email: shajianjunrjcom. More

Abstract

The treatment for metastatic castration-resistant prostate cancer patients remains a great challenge in the clinic and continuously demands discoveries of new targets and therapies. Here, we assess the function and therapeutic value of SIRT6 in metastatic castration-resistant prostate cancer.

Methods: The expression of SIRT6 was examined in prostate cancer tissue microarray by immunohistochemistry staining. The functions of SIRT6 and underlying mechanisms were elucidated by in vitro and in vivo experiments. We also developed an efficient method to silence SIRT6 by aptamer-modified exosomes carrying small interfering RNA and tested the therapeutic effect in the xenograft mice models.

Results: SIRT6 expression is positively correlated with prostate cancer progression. Loss of SIRT6 significantly suppressed proliferation and metastasis of prostate cancer cell lines both in vitro and in vivo. SIRT6-driven prostate cancer displays activation of multiple cancer-related signaling pathways, especially the Notch pathway. Silencing SIRT6 by siRNA delivered through engineered exosomes inhibited tumor growth and metastasis.

Conclusions: SIRT6 is identified as a driver and therapeutic target for metastatic prostate cancer in our findings, and inhibition of SIRT6 by engineered exosomes can serve as a promising therapeutic tool for clinical application.

Keywords: SIRT6, castration-resistant prostate cancer, Notch pathway, therapy, engineered exosomes

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