Abstract
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.
Highlights
Human prostate cancer (PCa) is the most malignant cancers affecting men worldwide with an increasing incidence and high mortality
Emerging evidence has shown that prostate cancer stem cells (PCSCs) are enriched by different phenotypic markers, including expression of CD44+, aldehyde dehydrogenase (ALDH), CD44+α2β1hiCD133+, PSA−/lo, and CD166+ (Chen et al, 2013; Skvortsov et al, 2018)
ALDHloCD44− cells in androgendeprived cultured conditions (Chen et al, 2016), suggesting that ALDHhiCD44+ PCa cells may enrich for PCSCs in tumor microenvironment (TME)
Summary
Human prostate cancer (PCa) is the most malignant cancers affecting men worldwide with an increasing incidence and high mortality. TME is vital for PCSCs. Recent studies have suggested that certain signaling pathways in TME may play a critical role in regulating PCSCs for their SC properties, metastatic traits and resistance to treatment, including the CXCL12/CXCR4 and WNT/β-catenin signaling pathways (Trautmann et al, 2014; Cojoc et al, 2015). Recent studies have suggested that certain signaling pathways in TME may play a critical role in regulating PCSCs for their SC properties, metastatic traits and resistance to treatment, including the CXCL12/CXCR4 and WNT/β-catenin signaling pathways (Trautmann et al, 2014; Cojoc et al, 2015)
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