image: (A) The expression of USP30-AS1 in normal tissues (n = 113) and breast cancer tissue (n = 1104), and the data were obtained from the TCGA breast cancer datasets. (B) The expression of USP30-AS1 in various subtypes of breast cancer, including triple-negative breast Cancer (n = 116), HER2+ enriched breast Cancer (n = 37), luminal A (n = 375) and luminal B breast Cancer (n = 166). (C) The expression of USP30-AS1 in breast cancer tissues and normal tissues. Data were obtained from GSE61304, Mann–Whitney U test. (D) USP30-AS1 expression levels were determined by qRT-PCR in MCF10A, MCF-7, and MDA-MB-231 cell lines. (E) The expression of USP30-AS1 in normal breast tissues (n = 84) and breast cancer tissues (n = 176) was determined by in situ hybridization. (F) CHIP Base, Gene Cards, and Animal TFDB websites were utilized to predict the transcription factors of USP30-AS1. (G) Correlation analysis of SPI1 and USP30-AS1 in breast cancer tissues (n = 1089). (H) The expression levels of SPI1 in normal (n = 113) and breast cancer tissues (n = 1104), and the data were obtained from TCGA breast cancer datasets. (I) The binding site of SPI1 in the promoter region of USP30-AS1 was obtained from JASPAR website. (J) qRT-PCR showed that knockdown of SPI1 down-regulates the expression of USP30-AS1. (K) Dual luciferase reporter assay was conducted to assess the effect of SPI1 siRNA on transcriptional activity of the USP30-AS1. (L) The interaction between SPI and USP30-AS1 promoter was determined by ChIP assay. TGGA, the cancer genome atlas.
Credit: Yapei Jiang, Weijie Liao, Qilei Xin, Ruonan Wang, Guanglan Lin, Jia Li, Zijian Yang, Shiyue Yang, Haowei Zhang, Xiaolin Li, Qian Peng, Yaou Zhang, Weidong Xie, Naihan Xu
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.
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