Abstract
SPOP, a substrate binding adaptor of E3 ubiquitin ligase Cullin3, is frequently mutated in human prostate cancer (PCa). However, whether and how SPOP is regulated at transcriptional level in PCa remain unclear. Here, we report that SPOP is down-regulated in PCa stem-like cells (CSCs) and tissues. Our study reveals that SPOP expression is repressed by TGF-β / SMAD signaling axis in PCa CSCs. SPOP promoter contains SMAD-binding elements (SBEs), which can interact with SMAD3. Moreover, TGF-β signaling inhibitor SB431542 promotes the SPOP expression and abrogates PCa stemness. Clinically, SPOP expression is downregulated in PCa patients, which is significantly related to a poor prognosis and lower survival rate. Thus, our findings uncover a mechanism of how SPOP expression is mediated in PCa CSCs via TGF-β/ SMAD3 signaling.
Highlights
Cancer stem cells (CSCs) have been identified in prostate cancer (PCa) as well as a number of other solid tumors [1]
We investigated the regulatory mechanism of Speckle-type POZ protein (SPOP) expression in PCa especially in terms of CSCs and found that SPOP expression is negatively regulated by SMAD3-mediated TGF-β signaling through the interaction between SMAD3 and its binding elements (SBEs) in the promoter of SPOP
TGF-β is a cytokine that can radiate signals from a heterodimeric receptor complex formed by the type I (TβRI) and the type II (TβRII) receptors to its downstream signal transducer, SMAD transcription factors, whose activation allows oncogenic instructions to be transmitted by deregulated signals in cancers [29]
Summary
Cancer stem cells (CSCs) have been identified in PCa as well as a number of other solid tumors [1]. Emerging evidence show that TGF-β has a complex and paradoxical role in cancer, acting as both a tumor suppressor and a factor that promotes cancer invasion and metastasis by suppressing immune responses [3,4,5]. TGF-β signaling plays an important role in regulating the function of cancer stem cells. Miao Y et al revealed that TGF-β-responding tumorinitiating stem cells (tSCs) are superior at resisting the transfer of T cells and facilitating tumor relapse using single-cell RNA sequencing (RNA-Seq) and lineage tracing [15]. It raises our enthusiasm regarding the role of TGF-β in maintaining self-renewal of PCa CSCs
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