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NEAT1 structural remodeling rewires MYC degradation pathway [MYC_CLIP_seq]

ABSTRACT: The MYC is a oncogenic driver in diverse human cancers. However, its intrinsically disordered structure has precluded direct pharmacological inhibition, posing a major challenge to targeting MYC-driven malignancies. This limitation has prompted the search for alternative strategies to modulate MYC activity. Recent findings suggest that MYC engage with cellular RNAs, revealing a previously underappreciated layer of regulatory control. Here, we identify the long noncoding RNA NEAT1_1 as a component of a MYC–NEAT1_1 protein–RNA complex that modulates MYC protein stability. While NEAT1 knockdown moderately increases MYC levels, we hypothesized that its structural conformation is critical to this regulatory function. To test this, we designed 88 antisense oligonucleotide mixmers targeting distinct structural regions of NEAT1_1. This screen uncovered both MYC-destabilizing and MYC-stabilizing oligonucleotides, without altering NEAT1_1 expression levels. A focused CRISPR screen identified UBR5 as an E3 ligase required for MYC-destabilizing mixmers induced MYC degradation, and we validated that these mixmers enhanced the MYC–UBR5 interaction, leading to more polyubiquitination of MYC. Our findings highlight a structure-guided mechanism by which a scaffold lncRNA governs the stability of an otherwise undruggable oncogene. This study provides proof-of-concept that RNA structural modulation can rewire protein turnover pathways, offering a promising therapeutic avenue for MYC-driven cancers.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309558 | GEO | 2026/08/25

REPOSITORIES: GEO

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