Tonic suppression of PCAT29 by the IL-6 signaling pathway in prostate cancer: Reversal by resveratrol

Abstract

Prostate cancer (PCa) is the second leading cause of cancer deaths in men. A better understanding of the molecular basis of prostate cancer proliferation and metastasis should enable development of more effective treatments. In this study we focused on the lncRNA, prostate cancer associated transcript 29 (PCAT29), a putative tumor suppressive gene. Our data show that the expression of PCAT29 was reduced in prostate cancer tumors compared to paired perinormal prostate tissues. We also observed substantially lower levels of PCAT29 in DU145 and LNCaP cells compared to normal prostate (RWPE-1) cells. IL-6, a cytokine which is elevated in prostate tumors, reduced the expression of PCAT29 in both DU145 and LNCaP cells by activating signal transducer and activator of transcription 3 (STAT3). One downstream target of STAT3 is microRNA (miR)-21, inhibition of which enhanced basal PCAT29 expression. In addition, we show that resveratrol is a potent stimulator of PCAT29 expression under basal condition and reversed the down regulation of this lncRNA by IL-6. Furthermore, we show that knock down of PCAT29 expression by siRNA in DU145 and LNCaP cells increased cell viability while increasing PCAT29 expression with resveratrol decreased cell viability. Immunohistochemistry studies showed increased levels of STAT3 and IL-6, but low levels of programmed cell death protein 4 (PDCD4), in prostate tumor epithelial cells compared to adjacent perinormal prostate epithelial cells. These data show that the IL-6/STAT3/miR-21 pathway mediates tonic suppression of PCAT29 expression and function. Inhibition of this signaling pathway by resveratrol induces PCAT29 expression and tumor suppressor function.

Regulation of Cell Signaling Pathways and miRNAs by Resveratrol in Different Cancers

“…Prostate cancer associated transcript 29 (PCAT29), a tumor suppressor, is frequently overexpressed in prostate cancer and downregulated by interleukin (IL-6) in DU145 and LNCaP cells [ 51 ]. Significantly enhanced phopsphorylated-STAT3 has been observed following treatment with IL-6 (10 ng/mL) in DU145 and LNCaP cells [ 51 ]. STAT3 knockdown induced an increase in PCAT29 expression in both DU145 and LNCaP cells.…”

“…Mechanistically, it was shown that STAT3 triggered the upregulation of miR-21, which consequently negatively regulated PCAT29 in PCa cells. Resveratrol repressed STAT signaling and stimulated expression of PCAT29 via repression of miR-21 [ 51 ] ( Figure 3 ). Further, protein inhibitor of activated STAT3 (PIAS3) has been found to be downregulated in medulloblastomas, and resveratrol shown to significantly upregulate PIAS3 in UW228-2, UW228-3, and DAOY cells with the repression of p-STAT3 levels [ 52 ].…”

Carcinogenesis in prostate cancer: The role of long non-coding RNAs

“…Another study [ 58 ] reported IL-6, a cytokine which is elevated in prostate tumours [ 59 ], reduced the expression of PCAT29 in both DU145 and LNCaP cell lines. IL-6 activates STAT3 which induces miR-21.…”

“…This interaction leads to the repression of PCAT29. Inhibition of miR-21 was shown to increase PCAT29 expression [ 58 ].…”

LncRNA PCAT29 suppresses cell proliferation, invasion, and migration in renal carcinoma by regulating FLOT1

“…MALAT1 is a common lncRNA and has been noted to be up-regulated in renal carcinoma and is correlated with tumor progression and a poor prognosis by interacting with Ezh2 and miR-205 [22,23] . LncRNA PCAT29 is an androgen-regulated tumor suppressor initially identified in prostate cancer and has been recently proven to be related to hepatitis virus-related hepatocellular carcinoma [15,24] . In this study, we determined that PCAT29 was down-regulated in renal carcinoma and inhibited tumor growth by suppressing cell proliferation viability, invasion, and migration, revealing its antitumor role in renal carcinoma.…”