Abstract
The Polycomb protein enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in advanced human prostate cancer (PCa), especially in lethal castration-resistant prostate cancer (CRPC). However, the signaling pathways that regulate EZH2 functions in PCa remain incompletely defined. Using EZH2 antibody-based RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to MALAT1, a long non-coding RNA (lncRNA) that is overexpressed during PCa progression. GST pull-down and RIP assays demonstrated that the 3' end of MALAT1 interacts with the N-terminal of EZH2. Knockdown of MALAT1 impaired EZH2 recruitment to its target loci and upregulated expression of EZH2 repressed genes. Further studies indicated that MALAT1 plays a vital role in EZH2-enhanced migration and invasion in CRPC cell lines. Meta-analysis and RT-qPCR of patient specimens demonstrated a positive correlation between MALAT1 and EZH2 expression in human CRPC tissues. Finally, we showed that MALAT1 enhances expression of PRC2-independent target genes of EZH2 in CRPC cells in culture and patient-derived xenografts. Together, these data indicate that MALAT1 may be a crucial RNA cofactor of EZH2 and that the EZH2-MALAT1 association may provide a new avenue for development new strategies for treatment of CRPC.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death among American men
Using enhancer of zeste homolog 2 (EZH2) antibodybased RNA immunoprecipitation-coupled high throughput sequencing (RIP-seq), we demonstrated that EZH2 binds to Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1), a long non-coding RNA that is overexpressed during prostate cancer (PCa) progression
HOTAIR is hardly detected in human PCa specimens [2], suggesting that other long non-coding RNA (lncRNA) may be important for EZH2 function in PCa
Summary
Prostate cancer (PCa) is the most commonly diagnosed malignancy and the second leading cause of cancer death among American men. Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced/ metastatic PCa. a significant portion of patients experience disease relapse and tumors eventually evolve into castration resistant prostate cancer (CRPC), which is the leading cause of PCa death at present [1]. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) lncRNA was originally identified as a prognostic factor of tumor development and metastasis in various types of human tumors such as glioma, lung, pancreatic and prostate cancer as well as esophageal squamous cell carcinoma [3,4,5,6]. MALAT1 was found positively correlated with Gleason score, the level of prostate specific antigen (PSA), tumor stage and castration resistance in PCa [7]. The role of MALAT1 in development and progression in PCa, especially CRPC remains elusive
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