The EZH2–PHACTR2–AS1–Ribosome Axis induces Genomic Instability and Promotes Growth and Metastasis in Breast Cancer

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.