Top

Published in:

Open Access 01-12-2024 | Prostate Cancer | Research

Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor

Authors: Daisuke Obinata, Kenichi Takayama, Mitchell G Lawrence, Daigo Funakoshi, Makoto Hara, Birunthi Niranjan, Linda Teng, Renea A Taylor, Gail P Risbridger, Satoru Takahashi, Satoshi Inoue

Published in: BMC Cancer | Issue 1/2024

Abstract

Background

Prostate cancer is dependent on androgen receptor (AR) signaling, and androgen deprivation therapy (ADT) has proven effective in targeting prostate cancer. However, castration-resistant prostate cancer (CRPC) eventually emerges. AR signaling inhibitors (ARSI) have been also used, but resistance to these agents develops due to genetic AR alterations and epigenetic dysregulation.

Methods

In this study, we investigated the role of OCT1, a member of the OCT family, in an AR-positive CRPC patient-derived xenograft established from a patient with resistance to ARSI and chemotherapy. We conducted a genome-wide analysis chromatin immunoprecipitation followed by sequencing and bioinformatic analyses using public database.

Results

Genome-wide analysis of OCT1 target genes in PDX 201.1 A revealed distinct OCT1 binding sites compared to treatment-naïve cells. Bioinformatic analyses revealed that OCT1-regulated genes were associated with cell migration and immune system regulation. In particular, C-terminal Binding Protein 2 (CTBP2), an OCT1/AR target gene, was correlated with poor prognosis and immunosuppressive effects in the tumor microenvironment. Metascape revealed that CTBP2 knockdown affects genes related to the immune response to bacteria. Furthermore, TISIDB analysis suggested the relationship between CTBP2 expression and immune cell infiltration in prostate cancer, suggesting that it may contribute to immune evasion in CRPC.

Conclusions

Our findings shed light on the genome-wide network of OCT1 and AR in AR-positive CRPC and highlight the potential role of CTBP2 in immune response and tumor progression. Targeting CTBP2 may represent a promising therapeutic approach for aggressive AR-positive CRPC. Further validation will be required to explore novel therapeutic strategies for CRPC management.

Available only for authorised users

Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate Cancer clinical trials Working Group. J Clin Oncol. 2008;26(7):1148–59.CrossRefPubMed

Obinata D, Takayama K, Takahashi S, Inoue S. Crosstalk of the androgen receptor with transcriptional collaborators: potential therapeutic targets for castration-resistant prostate Cancer. Cancers (Basel). 2017;9(3):22.CrossRefPubMed

Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, de Wit R, Mulders P, Chi KN, Shore ND, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97.CrossRefPubMed

Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33.CrossRefPubMedPubMedCentral

de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr., Saad F, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005.CrossRefPubMedPubMedCentral

Small EJ, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff JN, Olmos D, Mainwaring PN, Lee JY, Uemura H, et al. Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(11):1813–20.CrossRefPubMedPubMedCentral

Herberts C, Annala M, Sipola J, Ng SWS, Chen XE, Nurminen A, Korhonen OV, Munzur AD, Beja K, Schonlau E, et al. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer. Nature. 2022;608(7921):199–208.CrossRefPubMed

Obinata D, Lawrence MG, Takayama K, Choo N, Risbridger GP, Takahashi S, Inoue S. Recent discoveries in the androgen receptor pathway in castration-resistant prostate Cancer. Front Oncol. 2020;10:581515.CrossRefPubMedPubMedCentral

Ellis L, Loda M. LSD1: a single target to combat lineage plasticity in lethal prostate cancer. Proc Natl Acad Sci U S A. 2018;115(18):4530–1.CrossRefPubMedPubMedCentral

10.

Takayama KI, Kosaka T, Suzuki T, Hongo H, Oya M, Fujimura T, Suzuki Y, Inoue S. Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer. Nat Commun. 2021;12(1):3766.CrossRefPubMedPubMedCentral

11.

Obinata D, Takayama K, Fujiwara K, Suzuki T, Tsutsumi S, Fukuda N, Nagase H, Fujimura T, Urano T, Homma Y, et al. Targeting Oct1 genomic function inhibits androgen receptor signaling and castration-resistant prostate cancer growth. Oncogene. 2016;35(49):6350–8.CrossRefPubMed

12.

Bakht MK, Yamada Y, Ku SY, Venkadakrishnan VB, Korsen JA, Kalidindi TM, Mizuno K, Ahn SH, Seo JH, Garcia MM, et al. Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer. Nat Cancer. 2023;4(5):699–715.CrossRefPubMedPubMedCentral

13.

Sharma NL, Massie CE, Ramos-Montoya A, Zecchini V, Scott HE, Lamb AD, MacArthur S, Stark R, Warren AY, Mills IG, et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell. 2013;23(1):35–47.CrossRefPubMed

14.

Obinata D, Takayama K, Urano T, Murata T, Kumagai J, Fujimura T, Ikeda K, Horie-Inoue K, Homma Y, Ouchi Y, et al. Oct1 regulates cell growth of LNCaP cells and is a prognostic factor for prostate cancer. Int J Cancer. 2012;130(5):1021–8.CrossRefPubMed

15.

Yamamoto S, Takayama KI, Obinata D, Fujiwara K, Ashikari D, Takahashi S, Inoue S. Identification of new octamer transcription factor 1-target genes upregulated in castration-resistant prostate cancer. Cancer Sci. 2019;110(11):3476–85.CrossRefPubMedPubMedCentral

16.

Takayama KI, Suzuki Y, Yamamoto S, Obinata D, Takahashi S, Inoue S. Integrative genomic analysis of OCT1 reveals coordinated regulation of androgen receptor in advanced prostate Cancer. Endocrinology. 2019;160(2):463–72.CrossRefPubMed

17.

Porter LH, Lawrence MG, Wang H, Clark AK, Bakshi A, Obinata D, Goode D, Papargiris M, Mural, Clouston D, et al. Establishing a cryopreservation protocol for patient-derived xenografts of prostate cancer. Prostate. 2019;79(11):1326–37.CrossRefPubMed

18.

Lawrence MG, Obinata D, Sandhu S, Selth LA, Wong SQ, Porter LH, Lister N, Pook D, Pezaro CJ, Goode DL, et al. Patient-derived models of Abiraterone- and enzalutamide-resistant prostate Cancer reveal sensitivity to ribosome-directed therapy. Eur Urol. 2018;74(5):562–72.CrossRefPubMedPubMedCentral

19.

Obinata D, Funakoshi D, Takayama K, Hara M, Niranjan B, Teng L, Lawrence MG, Taylor RA, Risbridger GP, Suzuki Y, et al. OCT1-target neural gene PFN2 promotes tumor growth in androgen receptor-negative prostate cancer. Sci Rep. 2022;12(1):6094.CrossRefPubMedPubMedCentral

20.

Takayama K, Horie-Inoue K, Katayama S, Suzuki T, Tsutsumi S, Ikeda K, Urano T, Fujimura T, Takagi K, Takahashi S, et al. Androgen-responsive long noncoding RNA CTBP1-AS promotes prostate cancer. EMBO J. 2013;32(12):1665–80.CrossRefPubMedPubMedCentral

21.

McLean CY, Bristor D, Hiller M, Clarke SL, Schaar BT, Lowe CB, Wenger AM, Bejerano G. GREAT improves functional interpretation of cis-regulatory regions. Nat Biotechnol. 2010;28(5):495–501.CrossRefPubMedPubMedCentral

22.

Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, Cheng JX, Murre C, Singh H, Glass CK. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38(4):576–89.CrossRefPubMedPubMedCentral

23.

Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI, Young RA. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153(2):307–19.CrossRefPubMedPubMedCentral

24.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98–102.CrossRefPubMedPubMedCentral

25.

Ru B, Wong CN, Tong Y, Zhong JY, Zhong SSW, Wu WC, Chu KC, Wong CY, Lau CY, Chen I, et al. TISIDB: an integrated repository portal for tumor-immune system interactions. Bioinformatics. 2019;35(20):4200–2.CrossRefPubMed

26.

Ye C, Qin S, Qiu S, Zhao L, Miao J, Chen Y, Zhou T. A lncRNA-immune checkpoint-related gene signature predicts metastasis-free survival in prostate adenocarcinoma. Transl Androl Urol. 2022;11(12):1691–705.CrossRefPubMedPubMedCentral

27.

Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, Porta-Pardo E, Gao GF, Plaisier CL, Eddy JA, et al. The Immune Landscape of Cancer. Immunity. 2018;48(4):812–e830814.CrossRefPubMedPubMedCentral

28.

Takayama K, Suzuki T, Fujimura T, Urano T, Takahashi S, Homma Y, Inoue S. CtBP2 modulates the androgen receptor to promote prostate cancer progression. Cancer Res. 2014;74(22):6542–53.CrossRefPubMed

29.

Risbridger GP, Clark AK, Porter LH, Toivanen R, Bakshi A, Lister NL, Pook D, Pezaro CJ, Sandhu S, Keerthikumar S, et al. The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology. Nat Commun. 2021;12(1):5049.CrossRefPubMedPubMedCentral

30.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523.CrossRefPubMedPubMedCentral

31.

Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK, Chinnaiyan AM, Pienta KJ, Brown M. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell. 2007;27(3):380–92.CrossRefPubMedPubMedCentral

32.

Chinnadurai G. The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. Cancer Res. 2009;69(3):731–4.CrossRefPubMedPubMedCentral

33.

Di LJ, Byun JS, Wong MM, Wakano C, Taylor T, Bilke S, Baek S, Hunter K, Yang H, Lee M, et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun. 2013;4:1449.CrossRefPubMed

34.

Xu P, Yang JC, Chen B, Nip C, Van Dyke JE, Zhang X, Chen HW, Evans CP, Murphy WJ, Liu C. Androgen receptor blockade resistance with enzalutamide in prostate cancer results in immunosuppressive alterations in the tumor immune microenvironment. J Immunother Cancer. 2023;11(5):e006581.CrossRefPubMedPubMedCentral

35.

Nardone V, Botta C, Caraglia M, Martino EC, Ambrosio MR, Carfagno T, Tini P, Semeraro L, Misso G, Grimaldi A, et al. Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse. Cancer Biol Ther. 2016;17(11):1213–20.CrossRefPubMedPubMedCentral

36.

Xu P, Wasielewski LJ, Yang JC, Cai D, Evans CP, Murphy WJ, Liu C. The Immunotherapy and Immunosuppressive Signaling in Therapy-resistant prostate Cancer. Biomedicines. 2022;10(8):1778.CrossRefPubMedPubMedCentral

37.

Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, Choinzonov E, Kzhyshkowska J. Tumor-Associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Front Oncol. 2020;10:566511.CrossRefPubMedPubMedCentral

38.

Feng D, Shi X, Zhang F, Xiong Q, Wei Q, Yang L. Energy Metabolism-Related Gene Prognostic Index predicts biochemical recurrence for patients with prostate Cancer undergoing radical prostatectomy. Front Immunol. 2022;13:839362.CrossRefPubMedPubMedCentral

Title: Patient-derived castration-resistant prostate cancer model revealed CTBP2 upregulation mediated by OCT1 and androgen receptor
Authors: Daisuke Obinata
Kenichi Takayama
Mitchell G Lawrence
Daigo Funakoshi
Makoto Hara
Birunthi Niranjan
Linda Teng
Renea A Taylor
Gail P Risbridger
Satoru Takahashi
Satoshi Inoue
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Prostate Cancer
Prostate Cancer
Androgens
Published in: BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-024-12298-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer

High-content analysis identified synergistic drug interactions between INK128, an mTOR inhibitor, and HDAC inhibitors in a non-small cell lung cancer cell line

Role of beta-(1→3)(1→6)-D-glucan derived from yeast on natural killer (NK) cells and breast cancer cell lines in 2D and 3D cultures

Inflammatory markers predict survival in patients with postoperative urothelial carcinoma receiving tislelizumab (PD-1 inhibitor) adjuvant therapy

Prediction of esophageal cancer risk based on genetic variants and environmental risk factors in Chinese population

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study

Keynote webinar | Spotlight on antibody–drug conjugates in cancer