The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

Abstract

Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated.

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

“…However, with the widespread use of Enzalutamide and Abiraterone, a subset of CRPC patients developed neuroendocrine progression, termed as anti-AR treatmentinduced NEPC (t-NEPC) (72,73), accounting for more than 25-30% mortality of CRPC fatality (74). There were multiple mechanisms involved in NEPC progression, including attenuated control of transcriptional factors, metabolic alterations, aberrant activation of cellular kinases, long noncoding RNAs, transcriptional splicing, and epigenetic modifications (75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87). It is postulated that extensive stress of AR inhibition under the long-term ADT condition forced an epigenetic reprogramming of CRPC cells into neuroendocrinal trans-differentiation (88)(89)(90)(91)(92)(93).…”

Stanniocalcin 2 (STC2): a universal tumour biomarker and a potential therapeutical target

“…In addition, lncRNAs can function as molecular scaffolds that facilitate the interaction between mRNAs, miRNAs, DNAs and their relevant proteins like transcription factors, RNA-binding proteins and chromatin modifying complexes [ 134 ]. Therefore, lncRNAs are essential for various biological processes, and the dysregulation of lncRNAs presents in many pathological conditions, particularly, cancers [ 135 ]. The following are some examples of miRNAs and lncRNAs reported to regulate STC2 expression.…”

Characterization of Immune-Based Molecular Subtypes and Prognostic Model in Prostate Adenocarcinoma

“…Many studies have shown that some genes, also including non-coding RNAs (ncRNAs), largely contribute to tumorigenesis. For example, rAAV-based PTEN/CDKN1B delivery is promising for the development of novel therapeutics for PRAD because of its potential contribution [ 13 ], miR-338-3p may be a possible predictor of poor prognosis [ 14 ], some lncRNAs may be novel biomarkers in the diagnosis and prognosis of PRAD [ 15 ], and the lncRNA H19 regulates tumor plasticity in neuroendocrine prostate cancer [ 16 ]. These findings indicate the potential biological roles of some crucial genes in the occurrence and development of cancer, and further studies can be performed based on the potential crucial genes to explore the biomarkers in cancer diagnose and prognosis and even to characterize molecular classification.…”