CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1

AbstractTumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial–mesenchymal transition and breast cancer metastasis. Overall, our study establishes the CDK4/6–DUB3 axis as an important regulatory mechanism of breast cancer metastasis and provides a rationale for potential therapeutic interventions in the treatment of breast cancer metastasis.

Topics

No keywords indexed for this article. Browse by subject →

References

60

[1]

Bacac, M. & Stamenkovic, I. Metastatic cancer cell. Annu. Rev. Pathol. 3, 221–247 (2008). 10.1146/annurev.pathmechdis.3.121806.151523

[2]

Valastyan, S. & Weinberg, R. A. Tumor metastasis: molecular insights and evolving paradigms. Cell 147, 275–292 (2011). 10.1016/j.cell.2011.09.024

[3]

A Perspective on Cancer Cell Metastasis

Christine L. Chaffer, Robert A. Weinberg

Science 2011 10.1126/science.1203543

[4]

Gupta, P. B., Mani, S., Yang, J., Hartwell, K. & Weinberg, R. A. The evolving portrait of cancer metastasis. Cold Spring Harb. Symp. Quant. Biol. 70, 291–297 (2005). 10.1101/sqb.2005.70.033

[5]

Thiery, J. P. Metastasis: alone or together? Curr. Biol. 19, R1121–R1123 (2009). 10.1016/j.cub.2009.11.001

[6]

Braun, S. et al. A pooled analysis of bone marrow micrometastasis in breast cancer. N. Engl. J. Med. 353, 793–802 (2005). 10.1056/nejmoa050434

[7]

Chiang, A. C. & Massague, J. Molecular basis of metastasis. N. Engl. J. Med. 359, 2814–2823 (2008). 10.1056/nejmra0805239

[8]

Epithelial–mesenchymal plasticity in carcinoma metastasis

Jeff H. Tsai, Jing Yang

Genes & Development 2013 10.1101/gad.225334.113

[9]

Kang, Y. & Massague, J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell 118, 277–279 (2004). 10.1016/j.cell.2004.07.011

[10]

Chaffer, C. L. & Weinberg, R. A. How does multistep tumorigenesis really proceed? Cancer Discov. 5, 22–24 (2015). 10.1158/2159-8290.cd-14-0788

[11]

The basics of epithelial-mesenchymal transition

Raghu Kalluri, Robert A. Weinberg

Journal of Clinical Investigation 2009 10.1172/jci39104

[12]

Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits

Kornelia Polyak, Robert A. Weinberg

Nature Reviews Cancer 2009 10.1038/nrc2620

[13]

Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008). 10.1016/j.devcel.2008.05.009

[14]

EMT: 2016

M. Angela Nieto, Ruby Yun-Ju Huang, Rebecca A. Jackson et al.

Cell 2016 10.1016/j.cell.2016.06.028

[15]

Hay, E. D. An overview of epithelio-mesenchymal transformation. Acta Anat. 154, 8–20 (1995). 10.1159/000147748

[16]

Thiery, J. P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454 (2002). 10.1038/nrc822

[17]

Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009). 10.1016/j.cell.2009.11.007

[18]

Turley, E. A., Veiseh, M., Radisky, D. C. & Bissell, M. J. Mechanisms of disease: epithelial-mesenchymal transition--does cellular plasticity fuel neoplastic progression? Nat. Clin. Pract. Oncol. 5, 280–290 (2008). 10.1038/ncponc1089

[19]

Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7, 131–142 (2006). 10.1038/nrm1835

[20]

Fischer, K. R. et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 527, 472–476 (2015). 10.1038/nature15748

[21]

Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015). 10.1038/nature16064

[22]

Feng, Y. X. et al. Epithelial-to-mesenchymal transition activates PERK-eIF2alpha and sensitizes cells to endoplasmic reticulum stress. Cancer Discov. 4, 702–715 (2014). 10.1158/2159-8290.cd-13-0945

[23]

Davis, F. M., Stewart, T. A., Thompson, E. W. & Monteith, G. R. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol. Sci. 35, 479–488 (2014). 10.1016/j.tips.2014.06.006

[24]

Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004). 10.1101/gad.294104

[25]

Cadherin Cell Adhesion Receptors as a Morphogenetic Regulator

Masatoshi Takeichi

Science 1991 10.1126/science.2006419

[26]

Batlle, E. et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat. Cell Biol. 2, 84–89 (2000). 10.1038/35000034

[27]

Cano, A. et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol. 2, 76–83 (2000). 10.1038/35000025

[28]

Lamouille, S., Xu, J. & Derynck, R. Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15, 178–196 (2014). 10.1038/nrm3758

[29]

Peinado, H., Ballestar, E., Esteller, M. & Cano, A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol. Cell. Biol. 24, 306–319 (2004). 10.1128/mcb.24.1.306-319.2004

[30]

Dong, C. et al. G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer. J. Clin. Invest. 122, 1469–1486 (2012). 10.1172/jci57349

[31]

Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?

Héctor Peinado, David Olmeda, Amparo Cano

Nature Reviews Cancer 2007 10.1038/nrc2131

[32]

de Herreros, A. G., Peiro, S., Nassour, M. & Savagner, P. Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J. Mammary Gland Biol. Neoplasia 15, 135–147 (2010). 10.1007/s10911-010-9179-8

[33]

Zheng, H. et al. PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis. Cancer Cell 26, 358–373 (2014). 10.1016/j.ccr.2014.07.022

[34]

Vinas-Castells, R. et al. The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation. J. Biol. Chem. 285, 3794–3805 (2010). 10.1074/jbc.m109.065995

[35]

Zhou, B. P. et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat. Cell Biol. 6, 931–940 (2004). 10.1038/ncb1173

[36]

Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009). 10.1186/bcr2419

[37]

Rivadeneira, D. B. et al. Proliferative suppression by CDK4/6 inhibition: complex function of the retinoblastoma pathway in liver tissue and hepatoma cells. Gastroenterology 138, 1920–1930 (2010). 10.1053/j.gastro.2010.01.007

[38]

Dickson, M. A. et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J. Clin. Oncol. 31, 2024–2028 (2013). 10.1200/jco.2012.46.5476

[39]

Beaver, J. A. et al. FDA approval: palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, HER2-negative metastatic breast cancer. Clin. Cancer Res. 21, 4760–4766 (2015). 10.1158/1078-0432.ccr-15-1185

[40]

Finn, R. S. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 16, 25–35 (2015). 10.1016/s1470-2045(14)71159-3

[41]

Sun, M. et al. Activation of the ATM-Snail pathway promotes breast cancer metastasis. J. Mol. Cell Biol. 4, 304–315 (2012). 10.1093/jmcb/mjs048

[42]

MacPherson, M. R. et al. Phosphorylation of serine 11 and serine 92 as new positive regulators of human Snail1 function: potential involvement of casein kinase-2 and the cAMP-activated kinase protein kinase A. Mol. Biol. Cell 21, 244–253 (2010). 10.1091/mbc.e09-06-0504

[43]

Wu, Y. et al. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion. Cancer Cell 15, 416–428 (2009). 10.1016/j.ccr.2009.03.016

[44]

Zhang, K. et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat. Cell Biol. 15, 677–687 (2013). 10.1038/ncb2743

[45]

Vernon, A. E. & LaBonne, C. Tumor metastasis: a new twist on epithelial-mesenchymal transitions. Curr. Biol. 14, R719–R721 (2004). 10.1016/j.cub.2004.08.048

[46]

Tse, J. C. & Kalluri, R. Mechanisms of metastasis: epithelial-to-mesenchymal transition and contribution of tumor microenvironment. J. Cell Biochem. 101, 816–829 (2007). 10.1002/jcb.21215

[47]

Guarino, M., Rubino, B. & Ballabio, G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology 39, 305–318 (2007). 10.1080/00313020701329914

[48]

Ye, X. & Weinberg, R. A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression. Trends Cell Biol. 25, 675–686 (2015). 10.1016/j.tcb.2015.07.012

[49]

Tam, W. L. & Weinberg, R. A. The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat. Med. 19, 1438–1449 (2013). 10.1038/nm.3336

[50]

Delgado-Diaz, M. R., Martin, Y., Berg, A., Freire, R. & Smits, V. A. Dub3 controls DNA damage signalling by direct deubiquitination of H2AX. Mol. Oncol. 8, 884–893 (2014). 10.1016/j.molonc.2014.03.003

Showing 50 of 60 references

Cited By

122

BET proteins: Biological functions and therapeutic interventions

Jiawei Guo, Qingquan Zheng · 2023

Pharmacology & Therapeutics

The dark side of lipid metabolism in prostate and renal carcinoma: novel insights into molecular diagnostic and biomarker discovery

Nicola Antonio di Meo, Francesco Lasorsa · 2023

Expert Review of Molecular Diagnost...

Targeting Palbociclib-Resistant Estrogen Receptor-Positive Breast Cancer Cells via Oncolytic Virotherapy

Nadiia Lypova, Lilibeth Lanceta · 2019

Cancers

MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer

Matthew P. Goetz, Masakazu Toi · 2017

Journal of Clinical Oncology

Metrics

122

Citations

60

References

Details

Published: Jan 09, 2017
Vol/Issue: 8(1)
License: View

Authors

Department of Ophthalmology, Eye & Ear Nose Throat Hospital of Fudan University, Shanghai 200031, China; Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China; NHC Key Laboratory of Myopia (Fudan University), Shanghai 200031, China; Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai 200031, China

MOE Key Laboratory of Advanced Micro‐Structured Materials School of Physics Science and Engineering Tongji University Shanghai 200092 China

Department of Applied Chemistry, College of Science, Northeast Agricultural University, Harbin 150030, China

Y

Yang Han

Department of Infectious Disease, PUMC Hospital, CAMS and PUMC, Beijing

Inspire

Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130

Department of Oncology, Mayo Clinic, Rochester, Minnesota

Cite This Article

Tongzheng Liu, Jia Yu, Min Deng, et al. (2017). CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nature Communications, 8(1). https://doi.org/10.1038/ncomms13923

CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1

You May Also Like