Direct Interaction of β-catenin with Nuclear ESM1 Supports Stemness of Metastatic Prostate Cancer

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2020 Dec 21

PMID 33347625

Citations 23

Authors

Ke-Fan Pan

Wei-Jiunn Lee

Chun-Chi Chou

Yi-Chieh Yang

Yu-Chan Chang

Ming-Hsien Chien

Michael Hsiao

Kuo-Tai Hua

Affiliations

Soon will be listed here.

Abstract

Wnt/β-catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/β-catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here, we report that the expression of endothelial cell-specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated with prostate cancer stemness and progression by promoting Wnt/β-catenin signaling. Elevated ESM1 expression correlates with poor overall survival and metastasis. Accumulation of nuclear ESM1, instead of cytosolic or secretory ESM1, supports prostate cancer stemness by interacting with the ARM domain of β-catenin to stabilize β-catenin-TCF4 complex and facilitate the transactivation of Wnt/β-catenin signaling targets. Accordingly, activated β-catenin in turn mediates the nuclear entry of ESM1. Our results establish the significance of mislocalized ESM1 in driving metastasis in prostate cancer by coordinating the Wnt/β-catenin pathway, with implications for its potential use as a diagnostic or prognostic biomarker and as a candidate therapeutic target in prostate cancer.

Citing Articles

ESM1 promote proliferation, invasion and angiogenesis via Akt/mTOR and Ras pathway in kidney renal clear cell carcinoma.

Luo J, Yi T, Wang Y, Song W, Gao Z, Wang J Sci Rep. 2025; 15(1):4902.

PMID: 39929852 PMC: 11811180. DOI: 10.1038/s41598-024-82400-z.

Endothelial-secreted Endocan activates PDGFRA and regulates vascularity and spatial phenotype in glioblastoma.

Bastola S, Pavlyukov M, Sharma N, Ghochani Y, Nakano M, Muthukrishnan S Nat Commun. 2025; 16(1):471.

PMID: 39773984 PMC: 11707362. DOI: 10.1038/s41467-024-55487-1.

Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption.

Ouyang F, Li Y, Wang H, Liu X, Tan X, Xie G Adv Sci (Weinh). 2024; 11(47):e2406026.

PMID: 39494721 PMC: 11653682. DOI: 10.1002/advs.202406026.

Pre-operative prediction of BCR-free survival with mRNA variables in prostate cancer.

ODonnell A, Cronin M, Moghaddam S, Wolsztynski E PLoS One. 2024; 19(10):e0311162.

PMID: 39352906 PMC: 11444391. DOI: 10.1371/journal.pone.0311162.

Endocan, a novel glycoprotein with multiple biological activities, may play important roles in neurological diseases.

Liu S, Bai T, Feng J Front Aging Neurosci. 2024; 16:1438367.

PMID: 39328246 PMC: 11426085. DOI: 10.3389/fnagi.2024.1438367.

References

Robinson D, Van Allen E, Wu Y, Schultz N, Lonigro R, Mosquera J . Integrative clinical genomics of advanced prostate cancer. Cell. 2015; 161(5):1215-1228. PMC: 4484602. DOI: 10.1016/j.cell.2015.05.001. View

Xu W, Kimelman D . Mechanistic insights from structural studies of beta-catenin and its binding partners. J Cell Sci. 2007; 120(Pt 19):3337-44. DOI: 10.1242/jcs.013771. View

Krishnamurthy N, Kurzrock R . Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer Treat Rev. 2017; 62:50-60. PMC: 5745276. DOI: 10.1016/j.ctrv.2017.11.002. View

Jung Y, Cackowski F, Yumoto K, Decker A, Wang J, Kim J . CXCL12γ Promotes Metastatic Castration-Resistant Prostate Cancer by Inducing Cancer Stem Cell and Neuroendocrine Phenotypes. Cancer Res. 2018; 78(8):2026-2039. PMC: 6324566. DOI: 10.1158/0008-5472.CAN-17-2332. View

Grigoriu B, Depontieu F, Scherpereel A, Gourcerol D, Devos P, Ouatas T . Endocan expression and relationship with survival in human non-small cell lung cancer. Clin Cancer Res. 2006; 12(15):4575-82. DOI: 10.1158/1078-0432.CCR-06-0185. View

Schepeler T, Holm A, Halvey P, Nordentoft I, Lamy P, Riising E . Attenuation of the beta-catenin/TCF4 complex in colorectal cancer cells induces several growth-suppressive microRNAs that target cancer promoting genes. Oncogene. 2011; 31(22):2750-60. DOI: 10.1038/onc.2011.453. View

Truica C, Byers S, Gelmann E . Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res. 2000; 60(17):4709-13. View

Asally M, Yoneda Y . Beta-catenin can act as a nuclear import receptor for its partner transcription factor, lymphocyte enhancer factor-1 (lef-1). Exp Cell Res. 2005; 308(2):357-63. DOI: 10.1016/j.yexcr.2005.05.011. View

Kaltschmidt C, Banz-Jansen C, Benhidjeb T, Beshay M, Forster C, Greiner J . A Role for NF-κB in Organ Specific Cancer and Cancer Stem Cells. Cancers (Basel). 2019; 11(5). PMC: 6563002. DOI: 10.3390/cancers11050655. View

10.

Yokoyama N, Shao S, Hoang B, Mercola D, Zi X . Wnt signaling in castration-resistant prostate cancer: implications for therapy. Am J Clin Exp Urol. 2014; 2(1):27-44. PMC: 4219296. View

11.

Jamieson C, Sharma M, Henderson B . Targeting the β-catenin nuclear transport pathway in cancer. Semin Cancer Biol. 2014; 27:20-9. DOI: 10.1016/j.semcancer.2014.04.012. View

12.

Kypta R, Waxman J . Wnt/β-catenin signalling in prostate cancer. Nat Rev Urol. 2012; 9(8):418-28. DOI: 10.1038/nrurol.2012.116. View

13.

Shang S, Hua F, Hu Z . The regulation of β-catenin activity and function in cancer: therapeutic opportunities. Oncotarget. 2017; 8(20):33972-33989. PMC: 5464927. DOI: 10.18632/oncotarget.15687. View

14.

Kim Y, Han M, Oh S . The molecular mechanism for nuclear transport and its application. Anat Cell Biol. 2017; 50(2):77-85. PMC: 5509903. DOI: 10.5115/acb.2017.50.2.77. View

15.

Ravindranath A, Yuen H, Chan K, Grills C, Fennell D, Lappin T . Wnt-β-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer. Br J Cancer. 2011; 105(4):542-51. PMC: 3170969. DOI: 10.1038/bjc.2011.269. View

16.

Murillo-Garzon V, Kypta R . WNT signalling in prostate cancer. Nat Rev Urol. 2017; 14(11):683-696. DOI: 10.1038/nrurol.2017.144. View

17.

Liu C, Liu R, Zhang D, Deng Q, Liu B, Chao H . MicroRNA-141 suppresses prostate cancer stem cells and metastasis by targeting a cohort of pro-metastasis genes. Nat Commun. 2017; 8:14270. PMC: 5264244. DOI: 10.1038/ncomms14270. View

18.

Chesire D, Ewing C, Sauvageot J, Bova G, Isaacs W . Detection and analysis of beta-catenin mutations in prostate cancer. Prostate. 2000; 45(4):323-34. DOI: 10.1002/1097-0045(20001201)45:4<323::aid-pros7>3.0.co;2-w. View

19.

Mulholland D, Cheng H, Reid K, Rennie P, Nelson C . The androgen receptor can promote beta-catenin nuclear translocation independently of adenomatous polyposis coli. J Biol Chem. 2002; 277(20):17933-43. DOI: 10.1074/jbc.M200135200. View

20.

Hu W, Hu D, Xie L, Li Y, Majumdar S, Nonn L . Isolation and functional interrogation of adult human prostate epithelial stem cells at single cell resolution. Stem Cell Res. 2017; 23:1-12. PMC: 5581994. DOI: 10.1016/j.scr.2017.06.009. View