The EZH2-PHACTR2-AS1-Ribosome Axis induces Genomic Instability and Promotes Growth and Metastasis in Breast Cancer
Authors: Wei Zhao
Peng Wang
Wenhui Chu
Yenan Fu
Yunling Wang
Juan Du
Jing Zhang
Yu Yu
Lihua Qi
Jun Zhan
Hongquan Zhang
Wei-Guo Zhu
Xi Zhang
Journal: Cancer research (2020)
Discipline: CLINICAL MEDICINE
Keywords: EZH2; ribosome synthesis; PHACTR2-AS1; SUV39H1; H3K9 methylation
Affiliations: Department of Human Anatomy, Histology and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China., Guangdong Key Laboratory of Genome Instability and Human Disease, Shenzhen University Carson Cancer Center, Department of Biochemistry and Molecular Biology, Shenzhen University School of Medicine, Shenzhen, China., Department of Human Anatomy, Histology and Embryology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, Beijing, China.  .

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. 

Retracted: No

PubPeer comments:
 ![file] recycled blots , 
 Dear Macaria Combusta, Thank you for your interest in our research article, regarding your concern of recycling of images, let us clarify that these blots were intentionally used in FRBM article as the Prdx was probed by stripping the very same membrane used to generate RUNX2 and Actin blots from previous article in BBA-Mol Cell Res to show relative levels of Prdx and Runx2 . As you will also appreciate that lysates, time points and labeling (which you unfortunately cropped out) are also same. We however regret that we forgot to mention it while drafting the manuscript for which we apologize. Nonetheless, this reuse in no manner affects overall conclusion. Best, Arun , 
 As the Prdx1 bands do not appear to match the others, it would be best if the author provided the raw data here. If these bands are from different blots, it would very much affect the conclusion of the second paper. ,