The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

Abstract

Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm.NEPC is thought to originate from the trans-differentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/non-coding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drugresistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, microRNAs) play a key role in NEPC initiation and progression. Long non-coding RNAs (lncRNAs) represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively up-regulated in NEPCs and might interact with Polycomb genes. Our results indicate that lncRNAs can be exploited as new biomarkers and therapeutic targets for NEPC.Keywords: Neuroendocrine prostate cancer; MIAT; Long non-coding RNAs; Polycomb; Epigenetic/non-coding interactome; Trans-differentiation. Neuroendocrine Prostate Cancer: Clinical and Molecular FeaturesIn adult males, the prostate is a small acorn-shaped tissue with ductal-acinar histology surrounding the urethra at the base of the bladder. Its main function is to contribute secretory proteins to the seminal fluid [1]. The adult prostate is a pseudo-stratified epithelium composed of three main cell lineages (Fig.1, left panel): 1) secretory luminal cells are the predominant cell type; these cells express keratins (K8, K18), the androgen receptor (AR) and secretory proteins such as prostate-specific antigen (PSA) and prostatic specific acid phosphatase (PSAP);2) basal cells expressing K5 and K14 keratins and p63 are the second major cell type;3) neuroendocrine cells (NEC) expressing chromogranin A (CHGA), synaptophysin (SYP), and neuropeptides are scattered throughout the basal layer and comprise less than 1% of normal prostatic glandular epithelium [1][2][3].Prostate cancer (PCa) represents the second most frequently diagnosed neoplasm and is the sixth leading cause of cancer-related deaths in males worldwide [4,5]. In keeping with the composition of prostate epithelium, more than 95% of PCas are classified as adenocarcinomas, which show luminal phenotype and AR expression [6] (Fig.1, middle panel).Endogenous androgens, mainly produced by the testis, bind to the AR and fuel prostate adenocarcinoma proliferation [7]. For this reason, androgen-deprivation therapy (a.k.a. castration) is an effective therapeutic strategy for this disease. However, patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC) mainly via genetic and epigenetic alterations that facilitate ligand-independent AR activation, amplify the ARdependent signaling, or trigger different proliferative pathways [7]. CRPCs are characterized by substantially worse prognoses, but chemotherapeutics and newly approved hormonal treatments (e.g., Enzalutamide [8] and Abiraterone [9]) are still effective in p...

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

“…The patient characteristics are shown in Supplemental Table 1 (supplemental material available online with this article; https://doi.org/10.1172/JCI96218DS1). As shown in Figure 1A, the microarray analysis identified 158 upregulated and 142 downregulated lncRNAs from 7,419 analyzed lncRNAs in the MIBC tissues, including CASC9, MIAT, MEG3, and LINC01133, which are associated with human cancer progression (25)(26)(27)(28). Additionally, one lncRNA (LINC00958, RefSeq accession number NR_038904), Figure 1.…”

Upregulation of MIAT Regulates LOXL2 Expression by Competitively Binding MiR-29c in Clear Cell Renal Cell Carcinoma

“…However, there are few studies of MIAT in cancer. It has been reported that MIAT is selectively upregulated in neuroendocrine prostate cancer and may interact with polycomb genes [16]. Myc inhibition could increase the expression of MIAT in glioblastoma cells [31].…”

The role of long noncoding RNAs in cancer metastasis

“…For instance, snoRNAU50 is responsible for methylating residue C248 on the 28S rRNA subunit, and has been further implicated in supporting a tumor-suppressor phenotype in breast and prostate cancer [109] . However, SNORD26 and SNORD30 are important regulators of rRNA processing, and are expressed at higher abundance in metastatic prostate tumor samples, as compared to those having low Gleason scores, presumably to support the increased demand for protein synthesis required during tumorigenesis [17,110] . These studies support the notion that ncRNAs such as snoRNAs operate in a cell-context dependent manner, and therefore the continued investigation of specific ncRNAs responsible for modulating RNA splicing events, or the addition of RNA modifications that support a favorable cellular environment for processes such as metastasis to occur, are important.…”

“…The lncRNA myocardial infarction associated transcript (MIAT) has been linked to several chronic disorders including myocardial infarction [169,170] , paranoid schizophrenia [171] , and neuroendocrine-derived prostate cancers [110] . MIAT interacts with a number of epigenetic modifiers in neuronal crest cells including PRC1/2 and ZEB1 that when altered results in the modified migratory capacities of these cell lines [172] .…”

“…MIAT interacts with a number of epigenetic modifiers in neuronal crest cells including PRC1/2 and ZEB1 that when altered results in the modified migratory capacities of these cell lines [172] . MIAT is also disrupted in a number of cancer cell lines, and is expressed at significantly lower levels in grade I-II breast tumors, as compared to those considered high grade III-IV tumors [110] . MIAT also modulates the invasive capacities of breast cancer cells by mediating the ncRNA interaction networks between ZEB1 and certain miRNAs, such as miR-150 and miR-29 [173] .…”