TGF-β Signaling Regulates Expression and Promotes Prostate Cancer Cell Stemness

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2020 May 5

PMID 32364525

Citations 8

Authors

Chenchen Jiao

Tong Meng

Chenyu Zhou

Xinbo Wang

Ping Wang

Meiling Lu

Xiao Tan

Qing Wei

Xin Ge

Jiali Jin

Affiliations

Soon will be listed here.

Abstract

SPOP, a substrate binding adaptor of E3 ubiquitin ligase Cullin3, is frequently mutated in human prostate cancer (PCa). However, whether and how SPOP is regulated at transcriptional level in PCa remain unclear. Here, we report that is down-regulated in PCa stem-like cells (CSCs) and tissues. Our study reveals that SPOP expression is repressed by TGF-β / SMAD signaling axis in PCa CSCs. promoter contains SMAD-binding elements (SBEs), which can interact with SMAD3. Moreover, TGF-β signaling inhibitor SB431542 promotes the SPOP expression and abrogates PCa stemness. Clinically, SPOP expression is downregulated in PCa patients, which is significantly related to a poor prognosis and lower survival rate. Thus, our findings uncover a mechanism of how SPOP expression is mediated in PCa CSCs via TGF-β/ SMAD3 signaling.

Citing Articles

Stemness regulation in prostate cancer: prostate cancer stem cells and targeted therapy.

Liang H, Zhou B, Li P, Zhang X, Zhang S, Zhang Y Ann Med. 2024; 57(1):2442067.

PMID: 39711287 PMC: 11703425. DOI: 10.1080/07853890.2024.2442067.

SPOP downregulation promotes bladder cancer progression based on cancer cell-macrophage crosstalk via STAT3/CCL2/IL-6 axis and is regulated by VEZF1.

Li M, Cui Y, Qi Q, Liu J, Li J, Huang G Theranostics. 2024; 14(17):6543-6559.

PMID: 39479456 PMC: 11519788. DOI: 10.7150/thno.101575.

Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression.

Chen H, Fang S, Zhu X, Liu H Front Cell Dev Biol. 2024; 12:1412337.

PMID: 39092186 PMC: 11291335. DOI: 10.3389/fcell.2024.1412337.

SPOP regulates the expression profiles and alternative splicing events in human hepatocytes.

Dai J, Dong X, Chen Y, Xue W, Wang Q, Shang F Open Life Sci. 2023; 18(1):20220755.

PMID: 37941785 PMC: 10628592. DOI: 10.1515/biol-2022-0755.

miR-197-3p Promotes Osteosarcoma Stemness and Chemoresistance by Inhibiting SPOPL.

Zhang J, Wang S, Bai Y, Ali A, Deng J, Chen Y J Clin Med. 2023; 12(3).

PMID: 36769824 PMC: 9917813. DOI: 10.3390/jcm12031177.

References

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

Feng X, Derynck R . Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005; 21:659-93. DOI: 10.1146/annurev.cellbio.21.022404.142018. View

Tan P, Xu Y, Du Y, Wu L, Guo B, Huang S . SPOP suppresses pancreatic cancer progression by promoting the degradation of NANOG. Cell Death Dis. 2019; 10(11):794. PMC: 6797744. DOI: 10.1038/s41419-019-2017-z. View

Geng C, Rajapakshe K, Shah S, Shou J, Eedunuri V, Foley C . Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer. Cancer Res. 2014; 74(19):5631-43. PMC: 4209379. DOI: 10.1158/0008-5472.CAN-14-0476. View

Schmierer B, Hill C . TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007; 8(12):970-82. DOI: 10.1038/nrm2297. View

Zhuang M, Calabrese M, Liu J, Waddell M, Nourse A, Hammel M . Structures of SPOP-substrate complexes: insights into molecular architectures of BTB-Cul3 ubiquitin ligases. Mol Cell. 2009; 36(1):39-50. PMC: 2847577. DOI: 10.1016/j.molcel.2009.09.022. View

Lee J, Son M, Woolard K, Donin N, Li A, Cheng C . Epigenetic-mediated dysfunction of the bone morphogenetic protein pathway inhibits differentiation of glioblastoma-initiating cells. Cancer Cell. 2008; 13(1):69-80. PMC: 2835498. DOI: 10.1016/j.ccr.2007.12.005. View

Bierie B, Moses H . Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer. 2006; 6(7):506-20. DOI: 10.1038/nrc1926. View

Scheel C, Eaton E, Li S, Chaffer C, Reinhardt F, Kah K . Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell. 2011; 145(6):926-40. PMC: 3930331. DOI: 10.1016/j.cell.2011.04.029. View

10.

Wang X, Jin J, Wan F, Zhao L, Chu H, Chen C . AMPK Promotes SPOP-Mediated NANOG Degradation to Regulate Prostate Cancer Cell Stemness. Dev Cell. 2019; 48(3):345-360.e7. PMC: 7523188. DOI: 10.1016/j.devcel.2018.11.033. View

11.

Dumont N, Arteaga C . Targeting the TGF beta signaling network in human neoplasia. Cancer Cell. 2003; 3(6):531-6. DOI: 10.1016/s1535-6108(03)00135-1. View

12.

Nakano M, Kikushige Y, Miyawaki K, Kunisaki Y, Mizuno S, Takenaka K . Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. Oncogene. 2018; 38(6):780-793. DOI: 10.1038/s41388-018-0480-0. View

13.

An J, Wang C, Deng Y, Yu L, Huang H . Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep. 2014; 6(4):657-69. PMC: 4361392. DOI: 10.1016/j.celrep.2014.01.013. View

14.

Ikushima H, Todo T, Ino Y, Takahashi M, Miyazawa K, Miyazono K . Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell. 2009; 5(5):504-14. DOI: 10.1016/j.stem.2009.08.018. View

15.

Liu T, Xu F, Du X, Lai D, Liu T, Zhao Y . Establishment and characterization of multi-drug resistant, prostate carcinoma-initiating stem-like cells from human prostate cancer cell lines 22RV1. Mol Cell Biochem. 2010; 340(1-2):265-73. DOI: 10.1007/s11010-010-0426-5. View

16.

Zhang L, Peng S, Dai X, Gan W, Nie X, Wei W . Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells. Cancer Lett. 2017; 390:11-20. PMC: 5511705. DOI: 10.1016/j.canlet.2017.01.003. View

17.

Nishimura E, Suzuki M, Igras V, Du J, Lonning S, Miyachi Y . Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell. 2010; 6(2):130-40. PMC: 3437996. DOI: 10.1016/j.stem.2009.12.010. View

18.

Jeter C, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T . NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 2011; 30(36):3833-45. PMC: 3140601. DOI: 10.1038/onc.2011.114. View

19.

Gupta P, Onder T, Jiang G, Tao K, Kuperwasser C, Weinberg R . Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009; 138(4):645-659. PMC: 4892125. DOI: 10.1016/j.cell.2009.06.034. View

20.

Hu Z, Gupta J, Zhang Z, Gerseny H, Berg A, Chen Y . Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model. Hum Gene Ther. 2012; 23(8):871-82. PMC: 3413899. DOI: 10.1089/hum.2012.040. View