MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer.
Animals
Aurora Kinase A
/ metabolism
Basic Helix-Loop-Helix Transcription Factors
/ metabolism
Carcinogenesis
/ genetics
Carcinoma, Neuroendocrine
/ genetics
Cell Line, Tumor
Disease Progression
Enhancer of Zeste Homolog 2 Protein
/ metabolism
Gene Expression Regulation, Neoplastic
Homeodomain Proteins
/ metabolism
Humans
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors
/ metabolism
Male
Mice
Mice, Nude
Mucin-1
/ genetics
N-Myc Proto-Oncogene Protein
/ metabolism
Neoplastic Stem Cells
/ metabolism
Neuronal Plasticity
/ physiology
Octamer Transcription Factor-3
/ metabolism
POU Domain Factors
/ metabolism
Prostate
/ pathology
Prostatic Neoplasms
/ genetics
Prostatic Neoplasms, Castration-Resistant
/ genetics
Proto-Oncogene Proteins c-myc
SOXB1 Transcription Factors
/ metabolism
Signal Transduction
Synaptophysin
/ metabolism
Tumor Suppressor Protein p53
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 01 2020
17 01 2020
Historique:
received:
05
03
2019
accepted:
20
12
2019
entrez:
19
1
2020
pubmed:
19
1
2020
medline:
10
4
2020
Statut:
epublish
Résumé
Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.
Identifiants
pubmed: 31953400
doi: 10.1038/s41467-019-14219-6
pii: 10.1038/s41467-019-14219-6
pmc: PMC6969104
doi:
Substances chimiques
ASCL1 protein, human
0
Basic Helix-Loop-Helix Transcription Factors
0
Homeodomain Proteins
0
KLF4 protein, human
0
Klf4 protein, mouse
0
Kruppel-Like Factor 4
0
Kruppel-Like Transcription Factors
0
MUC1 protein, human
0
MYC protein, human
0
MYCN protein, human
0
Mucin-1
0
N-Myc Proto-Oncogene Protein
0
Octamer Transcription Factor-3
0
POU Domain Factors
0
POU5F1 protein, human
0
Proto-Oncogene Proteins c-myc
0
SOX2 protein, human
0
SOXB1 Transcription Factors
0
SYP protein, human
0
Synaptophysin
0
Tumor Suppressor Protein p53
0
transcription factor Brn-2
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Aurora Kinase A
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
338Subventions
Organisme : NCI NIH HHS
ID : R21 CA229716
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA232979
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA097098
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA233084
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166480
Pays : United States
Commentaires et corrections
Type : ErratumIn
Références
Puca, L., Vlachostergios, P. J. & Beltran, H. Neuroendocrine differentiation in prostate cancer: emerging biology, models, and therapies. Cold Spring Harb. Perspect. Med. 9, a030593 (2019).
pubmed: 29844220
Davies, A. H., Beltran, H. & Zoubeidi, A. Cellular plasticity and the neuroendocrine phenotype in prostate cancer. Nat. Rev. Urol. 15, 271–286 (2018).
pubmed: 29460922
Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).
pubmed: 29985747
pmcid: 6366813
Abida, W. et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl Acad. Sci. USA 116, 11428–11436 (2019).
pubmed: 31061129
Rickman, D. S., Beltran, H., Demichelis, F. & Rubin, M. A. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat. Med 23, 1–10 (2017).
pubmed: 28586335
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
pubmed: 28059768
pmcid: 5247742
Bishop, J. L. et al. The master neural transcription factor BRN2 is an androgen receptor-suppressed driver of neuroendocrine differentiation in prostate cancer. Cancer Discov. 7, 54–71 (2017).
pubmed: 27784708
Beltran, H. et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov. 1, 487–495 (2011).
pubmed: 22389870
pmcid: 3290518
Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).
pubmed: 26855148
pmcid: 4777652
Lee, J. et al. N-Myc drives neuroendocrine prostate cancer initiated from human prostate epithelial cells. Cancer Cell 29, 536–547 (2016).
pubmed: 27050099
pmcid: 4829466
Dardenne, E. et al. N-Myc induces an EZH2-mediated transcriptional program driving neuroendocrine prostate cancer. Cancer Cell 30, 563–577 (2016).
pubmed: 27728805
pmcid: 5540451
Berger, A. et al. N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer. J. Clin. Invest. 130, 3924–3940 (2019).
pubmed: 31260412
Kufe, D. Mucins in cancer: function, prognosis and therapy. Nat. Rev. Cancer 9, 874–885 (2009).
pubmed: 19935676
pmcid: 2951677
Kufe, D. MUC1-C oncoprotein as a target in breast cancer: activation of signaling pathways and therapeutic approaches. Oncogene 32, 1073–1081 (2013).
pubmed: 22580612
Rajabi, H. & Kufe, D. MUC1-C oncoprotein integrates a program of EMT, epigenetic reprogramming and immune evasion in human carcinomas. BBA Rev. Cancer 1868, 117–122 (2017).
Rajabi, H., Hiraki, M. & Kufe, D. MUC1-C activates polycomb repressive complexes and downregulates tumor suppressor genes in human cancer cells. Oncogene 37, 2079–2088 (2018).
pubmed: 29379165
pmcid: 5908737
Lapointe, J. et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc. Natl Acad. Sci. USA 101, 811–816 (2004).
pubmed: 14711987
Andrén, O. et al. MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden. Br. J. Cancer 97, 730–734 (2007).
pubmed: 17726465
pmcid: 2360377
Eminaga, O. et al. MUC1 expression by immunohistochemistry is associated with adverse pathologic features in prostate cancer: a multi-institutional study. PLoS ONE 11, e0165236 (2016).
pubmed: 27846218
pmcid: 5112958
Genitsch, V., Zlobec, I., Thalmann, G. N. & Fleischmann, A. MUC1 is upregulated in advanced prostate cancer and is an independent prognostic factor. Prostate Cancer Prostatic Dis. 19, 242–247 (2016).
pubmed: 27165976
Lin, X. et al. Overexpression of MUC1 and genomic alterations in its network associate with prostate cancer progression. Neoplasia 19, 857–867 (2017).
pubmed: 28930697
pmcid: 5605493
Wei, X., Xu, H. & Kufe, D. Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell 7, 167–178 (2005).
pubmed: 15710329
Hata, T. et al. MUC1-C activates the NuRD complex to drive dedifferentiation of triple-negative breast cancer cells. Cancer Res. 79, 5711–5722 (2019).
pubmed: 31519689
Rajabi, H. et al. MUC1-C represses the RASSF1A tumor suppressor in human carcinoma cells. Oncogene 38, 7266–7277 (2019).
pubmed: 31435022
Thalmann, G. N. et al. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 54, 2577–2581 (1994).
pubmed: 8168083
Epstein, J. I. et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol. 38, 756–767 (2014).
pubmed: 24705311
pmcid: 4112087
Wang, W. & Epstein, J. I. Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am. J. Surg. Pathol. 32, 65–71 (2008).
pubmed: 18162772
Bouillez, A. et al. Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas. Cancer Res. 76, 1538–1548 (2016).
pubmed: 26833129
pmcid: 4794417
Alam, M. et al. MUC1-C represses the Crumbs complex polarity factor CRB3 and downregulates the Hippo pathway. Mol. Cancer Res. 14, 1266–1276 (2016).
pubmed: 27658423
pmcid: 5136335
Xin, Z. et al. Inhibition of MUC1-C entering nuclear suppresses MYC expression and attenuates malignant growth in esophageal squamous cell carcinoma. Onco Targets Ther. 11, 4125–4136 (2018).
pubmed: 30050304
pmcid: 6056156
Stone, K. R., Mickey, D. D., Wunderli, H., Mickey, G. H. & Paulson, D. F. Isolation of a human prostate carcinoma cell line (DU 145). Int. J. Cancer 21, 274–281 (1978).
pubmed: 631930
Mertz, K. D. et al. Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model. Neoplasia 9, 200–206 (2007).
pubmed: 17401460
pmcid: 1838578
Ghandi, M. et al. Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature 569, 503–508 (2019).
pubmed: 31068700
pmcid: 6697103
Ku, S. Y. et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science 355, 78–83 (2017).
pubmed: 28059767
pmcid: 5367887
Rajabi, H. et al. MUC1-C activates EZH2 expression and function in human cancer cells. Sci. Rep. 7, 7481 (2017).
pubmed: 28785086
pmcid: 5547076
Hiraki, M. et al. MUC1-C activates BMI1 in human cancer cells. Oncogene 36, 2791–2801 (2017).
pubmed: 27893710
Kent, L. N. & Leone, G. The broken cycle: E2F dysfunction in cancer. Nat. Rev. Cancer 19, 326–338 (2019).
pubmed: 31053804
Akamatsu, S. et al. The placental gene PEG10 promotes progression of neuroendocrine prostate cancer. Cell Rep. 12, 922–936 (2015).
pubmed: 26235627
Dominguez, M. H., Ayoub, A. E. & Rakic, P. POU-III transcription factors (Brn1, Brn2, and Oct6) influence neurogenesis, molecular identity, and migratory destination of upper-layer cells of the cerebral cortex. Cereb. Cortex 23, 2632–2643 (2013).
pubmed: 22892427
Takahashi, K. & Yamanaka, S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 17, 183–193 (2016).
pubmed: 26883003
Joshi, M. D. et al. MUC1 oncoprotein is a druggable target in human prostate cancer cells. Mol. Cancer Ther. 8, 3056–3065 (2009).
pubmed: 19887552
pmcid: 2783220
Raina, D. et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol. Cancer Ther. 10, 806–816 (2011).
pubmed: 21421804
pmcid: 3092019
Raina, D. et al. Targeting cysteine-mediated dimerization of the MUC1-C oncoprotein in human cancer cells. Int J. Oncol. 40, 1643–1649 (2012).
pubmed: 22200620
Raina, D. et al. Characterization of the MUC1-C cytoplasmic domain as a cancer target. PLoS ONE 10, e0135156 (2015).
pubmed: 26267657
pmcid: 4534190
Raina, D. et al. Direct targeting of the MUC1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells. Cancer Res. 69, 5133–5141 (2009).
pubmed: 19491255
pmcid: 2721222
Banerjee, S. et al. MUC1c regulates cell survival in pancreatic cancer by preventing lysosomal permeabilization. PloS ONE 7, e43020 (2012).
pubmed: 22912777
pmcid: 3418232
Kharbanda, A. et al. Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells. Clin. Cancer Res. 20, 5423–5434 (2014).
pubmed: 25189483
pmcid: 4219601
GongSun, X. et al. Inhibition of MUC1-C regulates metabolism by AKT pathway in esophageal squamous cell carcinoma. J. Cell Physiol. 234, 12019–12028 (2019).
pubmed: 30523643
Hasegawa, M. et al. Intracellular targeting of the oncogenic MUC1-C protein with a novel GO-203 nanoparticle formulation. Clin. Cancer Res. 21, 2338–2347 (2015).
pubmed: 25712682
pmcid: 4433879
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).
pubmed: 26000489
pmcid: 4484602
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).
Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).
pubmed: 26563462
pmcid: 4771416
Akamatsu, S., Inoue, T., Ogawa, O. & Gleave, M. E. Clinical and molecular features of treatment-related neuroendocrine prostate cancer. Int. J. Urol. 25, 345–351 (2018).
pubmed: 29396873
Rajabi, H., Joshi, M. D., Jin, C., Ahmad, R. & Kufe, D. Androgen receptor regulates expression of the MUC1-C oncoprotein in human prostate cancer cells. Prostate 71, 1299–1308 (2011).
pubmed: 21308711
pmcid: 4916770
Rajabi, H. et al. MUC1-C oncoprotein confers androgen-independent growth of human prostate cancer cells. Prostate 72, 1659–1668 (2012).
pubmed: 22473899
pmcid: 3413781
Clermont, P. L. et al. Polycomb-mediated silencing in neuroendocrine prostate cancer. Clin. Epigenetics 7, 40 (2015).
pubmed: 25859291
pmcid: 4391120
Wei, X., Xu, H. & Kufe, D. Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res. 67, 1853–1858 (2007).
pubmed: 17308127
Kareta, M. S. et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis. Cell Stem Cell 16, 39–50 (2015).
pubmed: 25467916
Le Magnen, C., Shen, M. M. & Abate-Shen, C. Lineage plasticity in cancer progression and treatment. Annu Rev. Cancer Biol. 2, 271–289 (2018).
pubmed: 29756093
Gupta, P. B., Pastushenko, I., Skibinski, A., Blanpain, C. & Kuperwasser, C. Phenotypic plasticity: driver of cancer initiation, progression, and therapy resistance. Cell Stem Cell 24, 65–78 (2019).
pubmed: 30554963
Beltran, H. et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin. Cancer Res. 25, 6916–6924 (2019).
pubmed: 31363002
Li, Y., Liu, D., Chen, D., Kharbanda, S. & Kufe, D. Human DF3/MUC1 carcinoma-associated protein functions as an oncogene. Oncogene 22, 6107–6110 (2003).
pubmed: 12955090
pmcid: 4209839
Zhang, Y. et al. Numb and Numbl act to determine mammary myoepithelial cell fate, maintain epithelial identity, and support lactogenesis. FASEB J. 30, 3474–3488 (2016).
pubmed: 27383182
Watanabe, K. et al. Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev. Cell 29, 59–74 (2014).
pubmed: 24735879
pmcid: 4062651
Takahashi, H. et al. MUC1-C activates the TAK1 inflammatory pathway in colon cancer. Oncogene 34, 5187–5197 (2015).
pubmed: 25659581
pmcid: 4530107
Hata, T. et al. Targeting MUC1-C inhibits TWIST1 signaling in triple-negative breast cancer. Mol. Cancer Ther. 18, 1744–1754 (2019).
pubmed: 31308076
Shao, R. et al. Epithelial-to-mesenchymal transition and estrogen receptor alpha mediated epithelial dedifferentiation mark the development of benign prostatic hyperplasia. Prostate 74, 970–982 (2014).
pubmed: 24752964
Alonso-Magdalena, P. et al. A role for epithelial-mesenchymal transition in the etiology of benign prostatic hyperplasia. Proc. Natl Acad. Sci. USA 106, 2859–2863 (2009).
pubmed: 19196965
Perletti, G. et al. The association between prostatitis and prostate cancer. Systematic review and meta-analysis. Arch. Ital. Urol. Androl. 89, 259–265 (2017).
pubmed: 29473374
Panchamoorthy, G. et al. Targeting the human MUC1-C oncoprotein with an antibody-drug conjugate. JCI Insight 3, e99880 (2018).
pmcid: 6124453