A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression

Abstract

As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53-miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 39 untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.

Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death

“…35 GDF15 has been reported by multiple studies to be a target of p53 in response to both DNA damage and p53 induction by Nutlin-3, [4][5][6]20,36,37 and these and other results have attributed growthinhibitory and tumor-suppressive functions to GDF15. [7][8][9][10][11]38,39 However, other studies have found elevated expression of GDF15 in many human cancers, 15,[40][41][42] and high levels of GDF15 expression correspond to increased metastasis in both mouse models and human patients. [16][17][18][19][20]41,43 Although it is possible that GDF15 exerts pleiotropic effects on the growth of cancer cells, prior studies may have conflated the function of GDF15 with that of the embedded miR-3189.…”

“…25,45,13,17,46,44 Our results have identified miR-3189-3p as a miRNA that can kill cancer cells independently of p53. miR-34a, the most extensively studied p53-regulated miRNA, is involved in positive feedback loops with p53 by repressing the p53 inhibitors SIRT1 47 and HDM4, 11 but several studies suggest that its effects, unlike those of miR-3189-3p, depend on the presence of wild-type p53. 11,12,48 Our results indicate that miR-3189-3p also mediates a positive feedback loop in which p53 activation is sustained by downregulation of the known p53 inhibitors HDAC1 and HDAC3.…”

“…9 For instance, p53 has been shown to transactivate miR-34a after DNA damage, and miR-34a, in turn, represses the expression of pro-proliferative genes including MYC, CDK6, CCNA1 and HDM4. [10][11][12][13][14] Several p53-responsive miRNAs are intragenic and transcriptionally co-regulated with their host genes, such as miR-107/PANK1 15 and miR-29/PINT. 16,17 Recent highthroughput RNA sequencing studies have provided evidence supporting the existence of another such miRNA, the putative miR-3189, 18,19 embedded in the intron of the p53-inducible 20 TGF-β superfamily member 21 GDF15 on chromosome 19p13.11.…”

“…Recent reports suggest that some p53-regulated miRNAs including miR-34a and miR-29a potentiate p53 activity by targeting inhibitors of p53. 11,17 As a result, overexpression of these miRNAs upregulates p53 target genes even in unstressed cells and induces growth arrest and apoptosis in a p53-dependent manner. Several known inhibitors of p53 such as HDAC1, HDAC3, FOXM1, UBE3A, BCL6 and PRKRA were downregulated by miR-3189-3p (Supplementary Table S1).…”

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

“…MiRNAs are also frequently located near fragile sites in the genome, as well as commonly amplified regions or common breakpoints, indicating that genomic instability can also result in miRNA dysregulation (19). Aberrant expression or mutation of transcription factors may also result in dysregulation of miRNA expression in cancer, a phenomenon that has been extensively studied in relation to p53 (20)(21)(22)(23)(24). However, there is little information regarding the miRNAs regulated by CDX1 and how miRNAs contribute to the effects of CDX1 on stem cells and differentiation in CRC.…”