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

Oncogene volume 39, pages 6513–6528 (2020)Cite this article

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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.

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Fig. 1: DE-lncRNAs identification in GC tissues and low levels of PART1 expression correlate with poor prognosis.
Fig. 2: Forced expression of PART1 inhibits GC cell viability, invasion and migration in vitro and suppresses tumor growth and metastasis in vivo.
Fig. 3: Depletion of PART1 promotes GC cell viability, invasion and migration in vitro and enhances tumor growth and metastasis in vivo.
Fig. 4: PART1 downregulates genes associated with PI3K-Akt signaling but upregulates one tumor suppressor, PLZF.
Fig. 5: Nuclear PART1 binds specifically to AR and stimulates PLZF expression.
Fig. 6: PLZF depletion partially diminishes the PART1-initiated suppression effect on gastric cancer cell invasion.
Fig. 7: Cooccupancy of PLZF and EZH2 mediates the H3K27me3 mark on the chromatin at the PDGFB gene.
Fig. 8: Schematic model of PART1.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81772632, 81802943), Science Foundation of Peking University Cancer Hospital 2020-9, Beijing outstanding talent training program (No. 2018000021469G268), the interdisciplinary medicine Seed Fund of Peking University (No. BMU2018MX019), Special funds of the Ministry of Finance for Reform and Development and ‘San Ming’ Project of Shenzhen city (no. SZSM 201612051).

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  1. These authors contributed equally: S. Wang, J. Meng, G. Lyu, G. Ding

Authors and Affiliations

  1. Department of Biobank, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, P.R. China

    H. Han, G. Ding & Y. Hu

  2. Department of Clinical Laboratory, Peking University Cancer Hospital & Institute, Beijing, P.R. China

    S. Wang, J. Meng, L. Wang, W. Yang & Y. Lv

  3. Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, P.R. China

    G. Lyu

  4. Department of Central Laboratory, Peking University Cancer Hospital & Institute, Beijing, P.R. China

    L. Wu

  5. Department of Molecular Diagnostics, Peking University Cancer Hospital & Institute, Beijing, P.R. China

    S. Jia

  6. Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, P.R. China

    L. Zhang & J. Ji

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Han, H., Wang, S., Meng, J. et al. Long noncoding RNA PART1 restrains aggressive gastric cancer through the epigenetic silencing of PDGFB via the PLZF-mediated recruitment of EZH2. Oncogene 39, 6513–6528 (2020). https://doi.org/10.1038/s41388-020-01442-5

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