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.
Highlights
Ribosomal biogenesis is a highly ordered multistage process involving ribosomal DNA transcription, ribosomal protein synthesis, and ribosomal assembly [1]
LncRNA PHACTR2-AS1 is a target gene of EZH2 Similar to protein-coding genes, Long noncoding RNAs (lncRNA) are subject to epigenetic regulation, especially H3K27 methylation mediated by EZH2 [21]
Upon depletion of PHACTR2-AS1 induced by EZH2-mediated H3K27 methylation, rRNA transcription is reactivated, leading to increased ribosome synthesis and genomic instability, both of which promote cancer proliferation and metastasis (Fig. 7J)
Summary
Ribosomal biogenesis is a highly ordered multistage process involving ribosomal DNA (rDNA) transcription, ribosomal protein synthesis, and ribosomal assembly [1]. Moderate silencing of rDNA transcription is critical for genome stability. Disrupting rDNA silencing induces abnormal stimulation of rRNA synthesis, leading to uncontrolled cell proliferation or malignant cell transformation, and eventual tumorigenesis [3,4,5]. Some oncogenic and tumor-suppressive pathways modulate rDNA transcription [6,7,8,9]. Long noncoding RNAs (lncRNA) comprise a large class of regulatory RNAs without protein-coding potential that are >200 nucleotides long [10, 11].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
