Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity

Abstract

A widespread decrease of mature microRNAs is often observed in human malignancies giving them potential to act as tumor suppressors. Thus, microRNAs may be potential targets for cancer therapy. The global miRNA deregulation is often the result of defects in the miRNA biogenesis pathway, such as genomic mutation or aberrant expression/localization of enzymes and cofactors responsible of miRNA maturation. Alterations in the miRNA biogenesis machinery impact on the establishment and development of cancer programs. Accumulation of pri-microRNAs and corresponding depletion of mature microRNAs occurs in human cancers compared to normal tissues, strongly indicating an impairment of crucial steps in microRNA biogenesis. In agreement, inhibition of microRNA biogenesis, by depletion of Dicer1 and Drosha, tends to enhance tumorigenesis in vivo. The p53 tumor suppressor gene, TP53, is mutated in half of human tumors resulting in an oncogene with Gain-Of-Function activities. In this review we discuss recent studies that have underlined a role of mutant p53 (mutp53) on the global regulation of miRNA biogenesis in cancer. In particular we describe how a new transcriptionally independent function of mutant p53 in miRNA maturation, through a mechanism by which this oncogene is able to interfere with the Drosha processing machinery, generally inhibits miRNA processing in cancer and consequently impacts on carcinogenesis.

Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer

“…Recently, many studies of tumor-related miRNAs in different types of tumors have emerged; different miRNAs have been reported to modulate almost all physiological processes of tumor initiation, invasion, and metastasis [32,33]. In PDAC, similar to other tumors, the majority of tumor-related miRNAs are tumor suppressors; for example, the miR-200 family was found to be downregulated and play important roles in EMT, cell proliferation and apoptosis [34].…”

Dysregulated MicroRNA Expression Profiles and Potential Cellular, Circulating and Polymorphic Biomarkers in Non-Hodgkin Lymphoma

“…The processing pathway and biogenesis of miRNAs has been well characterised in other reviews [20,21] and will not be discussed here.…”

Unveiling the non-repair face of the Base Excision Repair pathway in RNA processing: A missing link between DNA repair and gene expression?

“…More importantly, deregulation of RBPs expression and activity has been linked to several malignancies. Among the panel of factors identified for example: DDX1, BRCA, ARS2, DR5, ADAR1, hRNP A1, KSRP, Lin 28, SMADs, YAP, ERα, ERβ, wtp53 and mutant p53 [79,80]. Of note, included in this list of RBPs, there are few DNA damage response (DDR) proteins [81].…”

“…p53 is able to interact with the Drosha complex through p68 increasing pri-miRNA biogenesis. Interestingly, transcriptionally inactive p53 mutants disrupt Drosha and p68 complex suppressing miRNA processing activity of Drosha by sequestering p68 cofactor [79,82].…”