Long noncoding RNA PART1 restrains aggressive gastric cancer through the epigenetic silencing of PDGFB via the PLZF-mediated recruitment of EZH2

Oncogene. 2020 Oct;39(42):6513-6528. doi: 10.1038/s41388-020-01442-5. Epub 2020 Sep 8.

Abstract

Current reports refer to the role of long noncoding RNA (lncRNA) prostate androgen-regulated transcript 1 (PART1) as a tumor suppressor in some types of cancer but as an oncogene in other kinds of cancer. In gastric cancer, it had been reported to be downregulated. However, the clinical significance and underlying mechanism of PART1 function in gastric cancer remains undefined. Here, seven differential expression levels of noncoding RNAs (DE-lncRNAs) were screened from gastric cancer through a probe reannotation of a human exon array. PART1 was selected for further study because of its high fold change number. In our cohort, PART1 was identified as a significant downregulated lncRNA in gastric cancer tissues by qPCR and in situ hybridization (ISH), and its low expression was significantly correlated with postoperative metastasis and short overall survival time after surgery. Through the results of gain-of-function experiments, PART1 was confirmed as a tumor suppressor that can decrease not only cell viability, migration, and invasion in vitro but also tumorigenesis and tumor metastasis in vivo. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) showed that PART1 interacts with androgen receptor (AR), and then, promyelocytic leukemia zinc finger (PLZF) is upregulated in an androgen-independent manner. In a chain reaction, chromatin immunoprecipitation (ChIP) assay additionally illustrated that PLZF upregulation increased the enrichment of EZH2 and H3K27 trimethylation in the platelet-derived growth factor (PDGFB) promotor, thereby inhibition of PDGFB and the subsequent PDGFRβ/PI3K/Akt signaling pathway. Based on these findings, we showed PART1 plays a tumor suppressor role by promoting PLZF expression followed by recruitment of EZH2 to mediate epigenetic PDGFB silencing and downstream PI3K/Akt inhibition, suggesting that PART1 has a key role in restraining the aggressive ability of GC cells and providing a novel perspective on lncRNAs in GC progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • DNA Methylation
  • Down-Regulation
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Histones / metabolism
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Promoter Regions, Genetic
  • Promyelocytic Leukemia Zinc Finger Protein / genetics*
  • Promyelocytic Leukemia Zinc Finger Protein / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-sis / genetics*
  • RNA, Long Noncoding / metabolism*
  • Signal Transduction / genetics
  • Stomach / pathology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Tissue Array Analysis
  • Up-Regulation
  • Xenograft Model Antitumor Assays

Substances

  • Histones
  • Promyelocytic Leukemia Zinc Finger Protein
  • Proto-Oncogene Proteins c-sis
  • RNA, Long Noncoding
  • ZBTB16 protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt