@article{e2f312b486934b979d5ed9a49cf12768,
title = "TCF7L1 regulates cytokine response and neuroendocrine differentiation of prostate cancer",
abstract = "Neuroendocrine differentiation (NED) is associated with WNT signaling activation and can be significantly observed after failure of androgen-deprivation therapy (ADT) for prostatic adenocarcinomas. Cytokine signaling is stimulated in NED prostate cancer; however, how ADT-upregulated WNT signaling promotes activation of cytokine signaling and contributes to NED of prostate cancer is poorly understood. In this study, we identified ADT-mediated upregulation of transcription factor 7 like 1 (TCF7L1), which increases the cytokine response and enhances NED of prostate cancer through interleukin (IL)-8/C-X-C motif chemokine receptor type 2 (CXCR2) signaling activation. ADT induced the secretion of WNT4 which upon engagement of TCF7L1 in prostate cancer cells, enhanced IL-8 and CXCR2 expressions. TCF7L1 directly binds to the regulatory sequence region of IL-8 and CXCR2 through WNT4 activation, thus upregulating IL-8/CXCR2 signaling-driven NED and cell motility. Analysis of prostate tissue samples collected from small-cell neuroendocrine prostate cancer (SCPC) and castration-resistant prostate cancer (CRPC) tumors showed an increased intensity of nuclear TCF7L1 associated with CXCR2. Our results suggest that induction of WNT4/TCF7L1 results in increased NED and malignancy in prostate cancer that is linked to dysregulation of androgen receptor signaling and activation of the IL-8/CXCR2 pathway.",
author = "Wen, {Yu Ching} and Liu, {Yen Nien} and Yeh, {Hsiu Lien} and Chen, {Wei Hao} and Jiang, {Kuo Ching} and Lin, {Shian Ren} and Jiaoti Huang and Michael Hsiao and Chen, {Wei Yu}",
note = "Funding Information: Activation of WNT signaling is highly associated with NED due to their impacts on neurodevelopment [44]. Our data support the drug-resistance role of WNT4 in PCa. We indentified the regulatory mechanism underlying the impact of WNT4 in TCF7L1-driven IL-8/ CXCR2 signaling on the NED of PCa after ADT. Our model was supported by ectopic WNT4 expression and the addition of exogenous WNT4. Both of these had indirect effects on WNT4 binding to secreted frizzled (FZD)-related protein (sFRP) family proteins or by replacing other endogenous WNT proteins with the opposite effect of binding to FZD receptors [55, 56]. We focused on WNT4 because it is more highly expressed in ADT-resistant cells. Our data confirmed that WNT4 gene silencing in MDV3100-resistant C4-2 and CSS-treated LNCaP cells reduced expressions of TCF7L1 and NE markers, which provides support for the link between endogenous WNT4 and TCF7L1 expressions in PCa cells under AR deprivation. Our study suggests that inhibition of AR-increased WNT4 upregulation activates TCF7L1-driven IL-8/ CXCR2 signaling which is associated with PCa NED progression. We explored the regulatory mechanisms of TCF7L1 which link suppression of the AR pathway with upregulated WNT4 signaling, and defined the roles of TCF7L1 in this crosstalk leading to progression of NED PCa by upregulating IL-8 and CXCR2. Publisher Copyright: {\textcopyright} 2021, The Author(s).",
year = "2021",
month = nov,
doi = "10.1038/s41389-021-00371-6",
language = "English",
volume = "10",
journal = "Oncogenesis",
issn = "2157-9024",
publisher = "Springer Nature",
number = "11",
}
