Enzalutamide-Induced Upregulation of PCAT6 Promotes Prostate Cancer Neuroendocrine Differentiation by Regulating miR-326/HNRNPA2B1 Axis

Abstract

Our previous studies have demonstrated that Enzalutamide-induced upregulation of long non-coding RNA p21 (lncRNA-p21) facilitates prostate cancer (PCa) neuroendocrine differentiation (NED). Given the important role of lncRNAs in PCa pathogenesis, and given that lots of lncRNAs are dys-regulated in neuroendocrine PCa (NEPC) patients, we next explored the biological function and underlying mechanism of lncRNA-PCAT6 (PCAT6) in mediating Enzalutamide-induced NED. The level of PCAT6 in Enzalutamide-treated PCa cells and NEPC samples were assessed using quantitative RT-PCR (qPCR). The effect of PCAT6 on PCa cell proliferation, invasion, and NED was evaluated through CCK-8, transwell, qPCR, western blot analysis, Xenograft mouse model, and in vivo lung metastasis model. We found that PCAT6 was highly expressed in NE-like cells (PC3, DU145, and NCI-H660) compared with androgen-sensitive LNCaP cells. PCAT6 was also highly expressed in NEPC tissues. Enzalutamide treatment resulted in a significant increase of PCAT6 level in a dose- and time-dependent fashion. Functionally, PCAT6 overexpression promoted NED of C4-2 cells, as evidenced by an increased expression of NE markers (NSE, ChgA, and SYP), whereas PCAT6 knockdown in NCI-H661 cells repressed NED. Furthermore, PCAT6 overexpression promoted PCa cell proliferation and invasion in vitro and in vivo. Mechanistically, PCAT6 functioned as competing endogenous (ce) RNA via absorbing miR-326, thus resulting in a de-suppression of Hnrnpa2b1 target gene. The current results demonstrate that PCAT6 acted as a tumor activator in PCa progression by sponging miR-326 and increasing Hnrnpa2b1 expression and that the PCAT6/miR-326/Hnrnpa2b1 signaling might be a new therapeutic target for PCa.

Regulation of Neuroendocrine-like Differentiation in Prostate Cancer by Non-Coding RNAs

“…Differential expression of lncRNA-p21 distinguished PCa patients from BPH [371]. A similar NEPC-promoting effect was also described for lncRNA-PCAT6 by sponging miR-326 [372]. lncRNA-PCAT6 was associated with prostate cancer metastases [373].…”

PCAT6 May Be a Whistler and Checkpoint Target for Precision Therapy in Human Cancers

“…The expression of PCAT6 is found to be aberrantly elevated in various human tumor tissues and cell lines compared with matched normal ones, including bladder cancer (BC) [ 21 , 24 , 25 ], breast cancer (BrCa) [ 26 , 27 ], cervical cancer (CC) [ 28 , 29 ], colorectal cancer (CRC) [ 30 , 31 ], gastrointestinal stromal tumor (GIST) [ 32 ], gastric cancer (GC) [ 33 , 34 ], glioblastoma (GBM) [ 35 ], hepatocellular carcinoma (HCC) [ 36 , 37 , 38 ], lung cancer (LC) [ 20 , 39 , 40 , 41 , 42 , 43 ], osteosarcoma (Osa) [ 44 , 45 , 46 ], ovarian cancer (OvCa) [ 47 , 48 ], cholangiocarcinoma (CCA) [ 49 ], pituitary adenoma (PA) [ 50 ], pancreatic ductal adenocarcinoma (PDAC) [ 51 ], and prostate cancer (PCa) [ 52 , 53 ]. In subsequent experiments on the biological functions of tumor cells, it has been revealed that a high level of PCAT6 has strong cancer-promoting effects, mainly including the promotion of cell proliferation, enhancement of migration, invasion and EMT process, as well as the inhibition of cell apoptosis.…”

“…In subsequent experiments on the biological functions of tumor cells, it has been revealed that a high level of PCAT6 has strong cancer-promoting effects, mainly including the promotion of cell proliferation, enhancement of migration, invasion and EMT process, as well as the inhibition of cell apoptosis. Meanwhile, PCAT6 has been shown to promote tumor growth and metastasis in xenograft mouse models ( Table 1 ) [ 26 , 29 , 30 , 38 , 39 , 40 , 43 , 44 , 46 , 50 , 52 , 53 , 54 ]. However, Amelia et al reported that the expression level of PCAT6 was opposite in lung tumor tissues and lung cancer cell lines compared with the normal control group [ 55 ].…”

“…LncRNAs play diverse functions depending on different subcellular or extracellular compartmental localizations. Most studies indicate that PCAT6 is primarily located in the cytoplasm of BC [ 25 ], GIST [ 32 ], GBM [ 35 ], Osa [ 44 , 45 ], PA [ 50 ], and Pca [ 52 ] cells. Cytoplasmic lncRNAs regulate genes at the translational and post-transcriptional levels, such as interaction with cytoplasmic proteins [ 58 ], and interaction with microRNAs to regulate downstream mRNA levels [ 59 , 60 , 61 , 62 , 63 ].…”

“…PCAT6 promotes HCC cell proliferation and invasion in vitro, and tumor growth in vivo by attenuating miR-326 and upregulating heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1) [ 38 ]. Moreover, enzalutamide induced PCAT6 also promotes PCa cell proliferation, metastasis, and neuroendocrine differentiation (NED) via the miR-326/HNRNPA2B1 axis in vitro or in vivo [ 52 ]. Several studies have clarified that HNRNPA2B1 can activate the PI3K/Akt/mTOR pathway [ 85 , 86 , 87 , 88 ], which further indicates that PCAT6 may induce this pathway through the ceRNA mechanism.…”