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The EZH2–PHACTR2–AS1–Ribosome Axis induces Genomic Instability and Promotes Growth and Metastasis in Breast Cancer
- Source :
- Cancer Research. 80:2737-2750
- Publication Year :
- 2020
- Publisher :
- American Association for Cancer Research (AACR), 2020.
-
Abstract
- Aberrant activation of histone methyltransferase EZH2 and ribosome synthesis strongly associate with cancer development and progression. We previously found that EZH2 regulates RNA polymerase III–transcribed 5S ribosomal RNA gene transcription. However, whether EZH2 regulates ribosome synthesis is still unknown. Here, we report that EZH2 promotes ribosome synthesis by targeting and silencing a long noncoding RNA PHACTR2-AS1. PHACTR2-AS1 directly bound ribosome DNA genes and recruited histone methyltransferase SUV39H1, which in turn triggered H3K9 methylation of these genes. Depletion of PHACTR2-AS1 resulted in hyperactivation of ribosome synthesis and instability of ribosomal DNA, which promoted cancer cell proliferation and metastasis. Administration of PHACTR2-AS1-30nt-RNA, which binds to SUV39H1, effectively inhibited breast cancer growth and lung metastasis in mice. PHACTR2-AS1 was downregulated in breast cancer patients, where lower PHACTR2-AS1 expression promoted breast cancer development and correlated with poor patient outcome. Taken together, we demonstrate that PHACTR2-AS1 maintains a H3K9 methylation-marked silent state of ribosomal DNA genes, comprising a regulatory axis that controls breast cancer growth and metastasis. Significance: These findings reveal that EZH2 mediates ribosomal DNA stability via silencing of PHACTR2-AS1, representing a potential therapeutic target to control breast cancer growth and metastasis.
- Subjects :
- 0301 basic medicine
Genome instability
Cancer Research
Lung Neoplasms
Apoptosis
Breast Neoplasms
Nerve Tissue Proteins
Mice, SCID
Biology
Ribosome
Genomic Instability
Metastasis
Mice
03 medical and health sciences
5S ribosomal RNA
0302 clinical medicine
Mice, Inbred NOD
Biomarkers, Tumor
Tumor Cells, Cultured
medicine
Animals
Humans
Enhancer of Zeste Homolog 2 Protein
RNA, Antisense
Cell Proliferation
Regulation of gene expression
Microfilament Proteins
EZH2
RNA
Prognosis
medicine.disease
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Histone methyltransferase
Disease Progression
Cancer research
Female
RNA, Long Noncoding
Ribosomes
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 80
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....05b7a24e8592bc6f0553da63f30e7cfa