Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment

Frontiers in Cell and Developmental Biology

Qiujun Tang¹  Juan Guo¹  Jing Zhang¹  Ping Peng¹  Bo Liu¹  Xin Chen¹  Jie Dong¹  Dong Kuang²  Jing Mao³  Qilin Li³  Weimin Chen³  Ding Xia⁴  Zhihua Wang⁴  Qiuhui Li⁵ 

[1] Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory for Oral Biomedicine of Ministry of Education (KLOBM), School and Hospital of Stomatology, Wuhan University, Wuhan, China;

关键词: prostate cancer stem cells;    prostate cancer;    tumor microenvironment;    PER3;    Wnt/β-catenin signaling;   

DOI  :  10.3389/fcell.2021.656981

来源: DOAJ

【 摘 要 】

Prostate cancer (PCa) cells are heterogeneous, containing a variety of cancer cells with phenotypical and functional discrepancies in the tumor microenvironment, where prostate cancer stem cells (PCSCs) play a vital role in PCa development. Our earlier studies have shown that ALDHhiCD44+ (DP) PCa cells and the corresponding ALDHloCD44– (DN) PCa cells manifest as PCSCs and non-PCSCs, respectively, but the underlying mechanisms regulating stemness of the PCSCs are not completely understood. To tackle this issue, we have performed RNA-Sequencing and bioinformatic analysis in DP (versus DN) cells in this study. We discovered that, PER3 (period circadian regulator 3), a circadian rhythm gene, is significantly downregulated in DP cells. Overexpression of PER3 in DP cells significantly suppressed their sphere- and colony-forming abilities as well as tumorigenicity in immunodeficient hosts. In contrast, knockdown of PER3 in DN cells dramatically promoted their colony-forming and tumor-initiating capacities. Clinically, PER3 is downregulated in human prostate cancer specimens and PER3 expression levels are highly correlated with the prognosis of the PCa patient. Mechanistically, we observed that low levels of PER3 stimulates the expression of BMAL1, leading to the phosphorylation of β-catenin and the activation of the WNT/β-catenin pathway. Together, our results indicate that PER3 negatively regulates stemness of PCSCs via WNT/β-catenin signaling in the tumor microenvironment, providing a novel strategy to treat PCa patients.

【 授权许可】

Unknown