This new study published in Genes & Diseases by researchers from Tsinghua University, Shenzhen University, Peking University Shenzhen Hospital, and Shenzhen Polytechnic University identifies ubiquitin-specific peptidase 30 antisense RNA 1 (USP30-AS1), a lncRNA transcribed antisense to the mitochondrial deubiquitinase USP30, as a key oncogenic regulator in breast cancer.

The researchers show that USP30-AS1 is significantly upregulated in breast cancer tissues and cell lines, with particularly high expression in aggressive subtypes. Transcriptional analyses further reveal that SPI1 acts as an upstream transcription factor driving USP30-AS1 expression, linking aberrant transcriptional activation to lncRNA-mediated oncogenic signaling.

Functional studies demonstrate that USP30-AS1 strongly promotes breast cancer cell proliferation, cell-cycle progression, and tumor growth in vivo. Silencing USP30-AS1 suppresses proliferation, induces apoptosis and senescence, and significantly reduces tumor growth in xenograft models. These effects are mediated primarily through repression of CDKN1A/p21, a critical cyclin-dependent kinase inhibitor that restrains cell-cycle progression.

Mechanistic investigations uncovered that USP30-AS1 exerts its oncogenic activity through spatially distinct but convergent regulatory pathways. In the cytoplasm, USP30-AS1 binds the RNA-binding protein HnRNPF, preventing HnRNPF from stabilizing p21 mRNA. This interaction accelerates p21 mRNA degradation, leading to reduced p21 protein levels and enhanced proliferation. In the nucleus, USP30-AS1 interacts with EZH2, the catalytic subunit of polycomb repressive complex 2. Rather than directly repressing p21, this interaction limits EZH2 recruitment to the c-Myc promoter, reducing repressive chromatin marks and thereby increasing c-Myc expression. Elevated c-Myc subsequently suppresses p21 transcription through a p53-independent mechanism.

Importantly, the study demonstrates that the oncogenic functions of USP30-AS1 are independent of its neighboring protein-coding gene USP30, highlighting the autonomous regulatory capacity of antisense lncRNAs. By coordinating post-transcriptional control in the cytoplasm with epigenetic regulation in the nucleus, USP30-AS1 establishes a robust regulatory network that converges on sustained p21 suppression.

Collectively, these findings position USP30-AS1 as a central integrator of multi-layered gene regulation in breast cancer. The dual-compartment activity of USP30-AS1 underscores the complexity of lncRNA function and highlights this molecule as a promising biomarker and potential therapeutic target for limiting tumor proliferation and progression in breast cancer.


Reference

Title of Original Paper: Nuclear and cytoplasmic USP30-AS1 coordinately regulate breast cancer progression through HnRNPF/p21 and EZH2/c-Myc/p21 axes

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101684

Funding Information:

• The National Key R&D Program of China (No. 2023YFA0914300, No. 2023YFA0914302)
• The National Natural Science Foundation of China (No. 31571418, No. 32200438)
• The Shenzhen Science and Technology Innovation Commission (No. JCYJ20160226185623304, No. JCYJ20240813142003005)
• Henan Provincial Science and Technology Research Project (No. 252102310403)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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