Abstract
Cancer stem cells (CSCs) are a small subset of stem-like cells inside tumors, which possess abilities of unlimited self-renewal, differentiation and proliferation. Extensive studies have suggested that CSCs are one of the major drivers of tumor initiation, metastasis, relapse and therapeutic resistance. Several regulatory networks including transcriptional programs and various signaling pathways tightly control the stemness, proliferation and differentiation of CSCs. Emerging evidence has indicated that post-translational modifications, especially ubiquitination, play a critical role in maintenance of CSC properties. In this review, we summarize current understandings on E3 ubiquitin ligase-mediated regulation of transcription factors and key signaling pathways involved in the regulation of CSCs, and discuss the strategy to target CSCs and E3 ubiquitin ligases for combating cancers.
Highlights
Tumor heterogeneity is a well-known phenomenon that tumor cells derived from different tumors or the same tumor exhibit distinct genotypes and phenotypes, which increases the complexity of cancer diagnosis and treatment [1]
In 1997, Bonnet and Dick provided the first evidence to demonstrate that Cancer stem cells (CSCs) exist in acute myeloid leukemia (AML)
In addition to the ubiquitination-mediated protein turnover, APC and DVL undergo K63-linked nonproteolytic poly-ubiquitination, while Axin can form K29linked poly-ubiquitination, all of which are important for the activation of Wnt signaling [81]. As most of these E3 ubiquitin ligases are deregulated in cancers, these studies offer a possible explanation for the aberrant activation of Wnt signaling in CSCs and various cancers
Summary
Tumor heterogeneity is a well-known phenomenon that tumor cells derived from different tumors or the same tumor exhibit distinct genotypes and phenotypes, which increases the complexity of cancer diagnosis and treatment [1]. Ubiquitination pathway is a critical determinant of CSC cell fate, which regulates the activation of pluripotency factors and stemness signaling pathways [28]. The E3 ligase WWP2 could target methylated Sox2 for ubiquitination and degradation, leading to cell differentiation [37].
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