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Canonical and non-Canonical Target-directed microRNA degradation controls cell fitness and transcriptional plasticity in breast cancer

ABSTRACT: MicroRNAs (miRNAs) play pivotal roles in cancer biology and hold promise as therapeutic targets. A recently discovered mechanism, termed target-directed miRNA degradation (TDMD), involves certain RNA transcripts ("triggers") inducing the degradation of miRNAs ("substrates"). The extent of TDMD regulation in human cancer and its implications in cancer phenotypes remain poorly understood. Here, we fill this gap identifying miRNA substrates that accumulate post-transcriptionally upon TDMD blockade in a panel of breast cancer cell lines. Our approach identified 31 high-confidence miRNA substrates, with a few miRNAs - including miR-7, miR-29b and miR-33a/b - controlled by degradation in multiple cell types. Combining transcriptome-wide mapping of miRNA:mRNA interactions by eCLIP with single cell RNA sequencing analysis of intratumor heterogeneity, we found that NREP limits the expression and activity of miR-29b in triple-negative breast cancer (TNBC) cell lines, fine tuning the transcriptional and phenotypic plasticity of cells along the epithelial-to-mesenchymal trajectory. Lastly, we demonstrated the existence of a non-canonical TDMD mechanism. Specifically, SERPINE1 triggers miR-30c-5p degradation in a ZSWIM8-independent manner in TNBC cell lines, contributing to aggressive cancer phenotypes such as cancer stem cell behavior, drug resistance, and cancer heterogeneity. In conclusion, our findings support a direct role for the TDMD mechanism in cancer biology and suggest a broader involvement of miRNA decay in human physiopathology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264419 | GEO | 2026/06/30

REPOSITORIES: GEO

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Canonical and non-Canonical Target-directed microRNA degradation controls cell fitness and transcriptional plasticity in breast cancer

Project description:MicroRNAs (miRNAs) play pivotal roles in cancer biology and hold promise as therapeutic targets. A recently discovered mechanism, termed target-directed miRNA degradation (TDMD), involves certain RNA transcripts ("triggers") inducing the degradation of miRNAs ("substrates"). The extent of TDMD regulation in human cancer and its implications in cancer phenotypes remain poorly understood. Here, we fill this gap identifying miRNA substrates that accumulate post-transcriptionally upon TDMD blockade in a panel of breast cancer cell lines. Our approach identified 31 high-confidence miRNA substrates, with a few miRNAs - including miR-7, miR-29b and miR-33a/b - controlled by degradation in multiple cell types. Combining transcriptome-wide mapping of miRNA:mRNA interactions by eCLIP with single cell RNA sequencing analysis of intratumor heterogeneity, we found that NREP limits the expression and activity of miR-29b in triple-negative breast cancer (TNBC) cell lines, fine tuning the transcriptional and phenotypic plasticity of cells along the epithelial-to-mesenchymal trajectory. Lastly, we demonstrated the existence of a non-canonical TDMD mechanism. Specifically, SERPINE1 triggers miR-30c-5p degradation in a ZSWIM8-independent manner in TNBC cell lines, contributing to aggressive cancer phenotypes such as cancer stem cell behavior, drug resistance, and cancer heterogeneity. In conclusion, our findings support a direct role for the TDMD mechanism in cancer biology and suggest a broader involvement of miRNA decay in human physiopathology.

2026-06-30 | GSE263552 | GEO

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Project description:MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form a complex that directs mRNA repression. One way that miRNAs are regulated is at the level of their stability. Some animal miRNAs are destabilized through a pathway in which pairing to specialized RNA transcripts recruits the ZSWIM8 E3 ubiquitin ligase, which polyubiquitinates AGO, leading to its degradation and exposure of the miRNA to cellular nucleases. We found that 22 miRNAs in C. elegans are sensitive to loss of EBAX-1, the ZSWIM8 ortholog in nematodes, implying that these 22 miRNAs might be subject to this pathway of target-directed miRNA degradation (TDMD). These miRNAs included the embryonic miR-35–42 family, as well as other miRNAs among the least stable in the worm, suggesting that TDMD is a major pathway of miRNA destabilization in the worm. The excess miR-35–42 molecules that accumulated in ebax-1 mutants caused increased repression of their predicted target mRNAs and underwent 3′ trimming over time. In general, however, miRNAs sensitive to loss of EBAX-1 did not have a consistent pattern of either trimming or tailing. A previous study reports that in contrast to TDMD substrates in mammals and flies, the 3′ region of miR-35 is not required for its destabilization, raising the question of whether the 3′ regions of other miRNAs are dispensable for EBAX-1 sensitivity in nematodes. To address this question, we replaced the 3′ region of another EBAX-sensitive miRNA, miR-43, and found that this replacement greatly reduced EBAX-sensitivity in the worm. Together, these findings broaden the implied biological scope of TDMD-like regulation of miRNA stability in animals, and indicate that the requirement for miRNA 3′ sequences in this process is variable in the worm.

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Widespread destabilization of C. elegans microRNAs by the E3 ubiquitin ligase EBAX-1 [miRNA-Seq]

2024-11-04 | GSE267367 | GEO

Target Directed miRNA degradation is pervasive in human cancer

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2022-01-31 | GSE168566 | GEO

Endogenous transcripts direct microRNA degradation in Drosophila, and this targeted degradation is required for proper embryonic development

Project description:MicroRNAs (miRNAs) typically direct degradation of their mRNA targets. However, five miRNA targets in vertebrate animals are reported to have unusual miRNA-binding sites that direct degradation of cognate miRNAs. Here, we identify six sites, five in mRNAs and one in a non-coding RNA named Marge, that serve this purpose in Drosophila cells or embryos, which shows that target-directed miRNA degradation (TDMD) shapes endogenous miRNA levels in some invertebrate animals. The six sites direct miRNA degradation without collateral target degradation, helping to explain the potency of this miRNA-degradation pathway. Mutations that disrupt this pathway in Drosophila are lethal, with many flies dying as embryos. Derepression of miR-3 and its paralog miR-309 is responsible for some of this lethality, whereas the loss of Marge-directed degradation of miR-310 miRNAs causes defects in embryonic cuticle development. Thus, TDMD is strongly implicated in the viability of an animal and is required for its proper development.

2022-09-14 | GSE196837 | GEO

Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-dependent miRNA degradation mechanism [RNA-Seq]

Project description:Little is known about how miRNAs are turned over, in particular in mammalian cells. A target-dependent miRNA degradation mechanism (TDMD) has been recently suggested, in which RNA targets may induce miRNA degradation. However, endogenous RNA targets involved in TDMD have not been yet identified. During serum stimulation of quiescent fibroblasts, a deep change of miRNA expression occurs in few hours. We scanned the mammalian genome for targets eligible for TDMD and found a dominant miRNA:target pair, consisting of a target (SerpinE1) extraordinarily induced upon serum stimulation and two matched miRNAs (miR-30b/c) quickly downregulated. We verified directly the occurrence of TDMD by interfering specifically with the miR-:target interaction, keeping target and miRNA expression at endogenous levels, using CRISPR/cas9 mediated deletion of the miR-30 responsive element (MRE) of SerpinE1. In MRE-KO cells, we observed the stabilization of the predicted miRNAs, with no evidence of alterations in precursors or unrelated miRNAs, suggesting that TDMD is occurring and has been disrupted by a single MRE deletion. At molecular level miRNA degradation occurs within physiological ranges of target expression (upon 1000 copies per cells) and is accompanied by modification on 3’ends (tailing, mostly through adenylation). TDMD suppression was sufficient to shift the activity of miR-30b/c towards other shared targets, modulate significantly gene expression and, thus, influence cellular functions, including cell proliferation, apoptosis, and adhesion. In conclusion, these data strongly support the existence of a novel and sophisticated regulatory layer of miRNA and gene expression mediated by specific endogenous targets in mammalian cells.

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Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-dependent miRNA degradation mechanism [miRNA-Seq]

2018-06-26 | GSE104598 | GEO

Endogenous transcripts control miRNA levels and activity in mammalian cells by a target-dependent miRNA degradation mechanism [RNA-Seq_2]

2018-06-26 | GSE112578 | GEO

Plagl1 and Lrrc58 control mammalian body size by triggering target-directed microRNA degradation of miR-322 and miR-503 [RNA-seq]

Project description:Precise control of microRNA (miRNA) expression is critical for normal development. An important mechanism of miRNA regulation is target-directed microRNA degradation (TDMD), a pathway in which the binding of miRNAs to specialized trigger RNAs induces ubiquitylation and decay of associated Argonaute (AGO) proteins by the ZSWIM8 ubiquitin ligase. ZSWIM8-deficient mice exhibit reduced body size, cardiopulmonary and neurodevelopmental defects, and perinatal lethality. Despite widespread dysregulation of miRNAs in these animals, the vast majority of presumptive trigger RNAs that induce decay of ZSWIM8-regulated miRNAs remain undefined. Here, using AGO crosslinking and sequencing of hybrids (AGO-CLASH), a high-throughput method for identifying miRNA binding sites, we report the identification of Plagl1 as a trigger for TDMD of miR-322-5p, and Lrrc58 and Malat1 as TDMD triggers for miR-503-5p in mouse embryonic fibroblasts (MEFs). In mice, deletion of the miR-322-5p and miR-503-5p trigger sites in the Plagl1 and Lrrc58 3' UTRs, respectively, abrogated TDMD of these miRNAs and resulted in miR-322/503-dependent embryonic growth restriction, recapitulating a key feature of the Zswim8—/— phenotype. Thus, these results demonstrate that the transcripts encoding Plagl1 and Lrrc58 regulate mammalian body size by inducing degradation of miR-322-5p and miR-503-5p and provide a valuable resource for identification of additional TDMD triggers.

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