Risk SNP-Mediated Promoter-Enhancer Switching Drives Prostate Cancer through lncRNA PCAT19.

The prostate cancer (PCa) risk-associated SNP rs11672691 is positively associated with aggressive disease at diagnosis. We showed that rs11672691 maps to the promoter of a short isoform of long noncoding RNA PCAT19 (PCAT19-short), which is in the third intron of the long isoform (PCAT19-long). The risk variant is associated with decreased and increased levels of PCAT19-short and PCAT19-long, respectively. Mechanistically, the risk SNP region is bifunctional with both promoter and enhancer activity. The risk variants of rs11672691 and its LD SNP rs887391 decrease binding of transcription factors NKX3.1 and YY1 to the promoter of PCAT19-short, resulting in weaker promoter but stronger enhancer activity that subsequently activates PCAT19-long. PCAT19-long interacts with HNRNPAB to activate a subset of cell-cycle genes associated with PCa progression, thereby promoting PCa tumor growth and metastasis. Taken together, these findings reveal a risk SNP-mediated promoter-enhancer switching mechanism underlying both initiation and progression of aggressive PCa.

Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus.

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic.

lncRNA PCAT19 promotes the proliferation of laryngocarcinoma cells via modulation of the miR-182/PDK4 axis.

The mechanism of tumorigenesis has not been fully identified in laryngeal cancer, which accounts for one fourth of patents with head and neck tumors. Long noncoding RNA PCAT19 has been shown to participate in the prostate cancer progression. However, little is known about the role of PCAT19 in the tumorigenesis of laryngeal cancer. In our study, it was shown that the expression levels of PCAT19 was increased in laryngeal tumor tissues and associated with decreased overall survival. Using laryngeal cancer cells lines HEp-2 and AMC-HN-8, it was demonstrated that knockdown of PCAT19 decreased the cell proliferation, increased the mitochondrial respiration, and inhibited the glycolysis. In detail, it showed that the PDK4 expression and PDHE1α phosphorylation levels were decreased upon the PCAT19 knockdown. Further studies indicated that miR-182 functioned as the bridge between PCAT19 and PDK4, which could also regulate the cellular metabolism thus affecting the cell proliferation. Furthermore, it was shown that the PCAT19/miR-182/PDK4 axis existed and regulated cell proliferation by modulating glycolysis and mitochondrial respiration. Finally, we showed that the PCAT19 knockdown decreased the tumor growth in vivo, possibly through regulating the miR-182/PDK4 axis. In conclusion, we demonstrated that lncRNA PCAT19 promoted cell proliferation and tumorigenesis by modulating the miR-182/PDK4 axis and the metabolism balance. PCAT19 might become a promising new target for laryngeal cancer therapeutics.

LncRNA-PCat19 acts as a ceRNA of miR-378a-3p to facilitate microglia activation and accelerate chronic neuropathic pain in rats by promoting KDM3A-mediated BDNF demethylation.

The pathogenesis of neuropathic pain (NP) is complex, and there are various pathological processes. Previous studies have suggested that lncRNA PCAT19 is abnormally expressed in NP conduction and affects the occurrence and development of pain. The aim of this study is to analyze the role and mechanism of PCAT19 in NP induced by chronic compressive nerve injury (CCI) in mice. In this study, C57BL/6 mice were applied to establish the CCI model. sh-PCAT19 was intrathecally injected once a day for 5 consecutive days from the second day after surgery. We discovered that PCat19 level was gradually up-regulated with the passage of modeling time. Downregulation of Iba-1-positive expression, M1/M2 ratio of microglia, and pro-inflammatory factors in the spinal cords of CCI-mice after PCat19 knock-downed was observed. Mechanically, the expression of miR-378a-3p was negatively correlated with KDM3A and PCat19. Deletion of KDM3A prevented H3K9me2 demethylation of BDNF promoter and suppressed BDNF expression. Further, KDM3A promotes CCI-induced neuroinflammation and microglia activation by mediating Brain-derived neurotrophic factor (BDNF) demethylation. Together, the results suggest that PCat19 may be involved in the development of NP and that PCat19 shRNA injection can attenuate microglia-induced neuroinflammation by blocking KDM3A-mediated demethylation of BDNF and BDNF release.

LncRNA PCAT19 induced by SP1 and acted as oncogene in gastric cancer competitively binding to miR429 and upregulating DHX9.

Increasing evidence suggests that long non-coding RNAs (lncRNAs) are crucial in cancer biological processes. To investigate if lncRNA contributes to gastric cancer (GC), we conducted a bioinformatics analysis in human microarray datasets, and the results showed that lncRNA prostate cancer-associated transcript 19 (PCAT19) was upregulated in GC. Quantitative reverse-transcriptase PCR and in situ hybridization assays also revealed that PCAT19 was upregulated in GC tissues. The PCAT19 expression in GC was significantly related to tumor size, lymph node metastasis, and pathological stage. Moreover, patients with higher PCAT19 expression levels were more likely to have a poor prognosis for overall survival. The knockdown of PCAT19 by siRNA significantly suppressed the proliferation and invasion of GC cells. The cell distribution of PCAT19 in GC cells was examined by fluorescence in situ hybridization assay, and the results showed that it was mainly located in the cytoplasm. Mechanistically, PCAT19 sponges miR-429 and promotes DHX9 expression. In addition, the transcription factor SP1 is involved in PCAT19 activation. Our results demonstrate that lncRNA PCAT19 is induced by SP1 and acts as an oncogene in GC that competitively binds to miR429 and upregulates DHX9.

Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2.

In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19, which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation.

Oncogenic regulatory circuits driven by 19q13 rs11672691 underlies prostate cancer aggressiveness.

The 19q13 allele rs11672691 has been reproducibly found in association with aggressive form of prostate cancer, yet the underlying mechanism remains totally unknown. We have recently uncovered a mechanism by which rs11672691 influenced a novel oncogenic regulatory circuit, including HOXA2, PCAT19 and CEACAM21, thereby contributing to prostate cancer aggressiveness.