The role of miRNA biogenesis and DDX17 in tumorigenesis and cancer stemness

Abstract

Cancer stemness represents one of the major mechanisms that predispose patients to tumor aggressiveness, metastasis, and treatment resistance. MicroRNA biogenesis is an important process controlling miRNA processing and maturation. Deregulation of miRNA biogenesis can lead to tumorigenesis and cancer stemness. DDX17 is a co-factor of the miRNA microprocessor. Misregulation of DDX17 can be associated with cancer stemness. K63-linked polyubiquitination of DDX17 presents a concerted mechanism of decreased synthesis of stemness-inhibiting miRNAs and increased transcriptional activation of stemness-related gene expression. K63-linked polyubiquitination of HAUSP serves as a scaffold to anchor HIF-1α, CBP, the mediator complex, and the super-elongation complex to enhance HIF-1α-induced gene transcription. Recent progress in RNA modifications shows that RNA N6-methyladenosine (m6A) modification is a crucial mechanism to regulate RNA levels. M6A modification of miRNAs can also be linked to tumorigenesis and cancer stemness. Overall, miRNA biogenesis and K63-linked polyubiquitination of DDX17 play an important role in the induction of cancer stemness. Delineation of the mechanisms and identification of suitable targets may provide new therapeutic options for treatment-resistant cancers.

Keywords: Cancer stemness; DDX17; HAUSP; K63-linked polyubiquitination; m6A; miRNA biogenesis.

Fig. 1

Co-factors that regulate miRNA biogenesis. Positive and negative regulatory factors are summarized in the figure. The detailed mechanisms are described in the text.

Fig. 2

Concerted regulation of miRNA biogenesis and transcriptional activation that mediates cancer stemness through K63-linked polyubiquitination of DDX17.