Skip to main content
SpringerLink
Log in

Dual Roles for Epithelial Splicing Regulatory Proteins 1 (ESRP1) and 2 (ESRP2) in Cancer Progression

  • Chapter
  • First Online:
Protein Reviews

Part of the book series: Advances in Experimental Medicine and Biology ((PROTRE,volume 925))

Abstract

Epithelial splicing regulatory protein 1 (ESRP1) and 2 (ESRP2) are members of the hnRNP family of RNA binding proteins that regulate alternative splicing events associated with epithelial phenotypes. These proteins play crucial roles during organogenesis, including craniofacial and epidermal development as well as branching morphogenesis in the lungs and salivary glands. Recent reports have also addressed their roles during cancer progression. Expression of ESRP proteins is low in normal epithelium but upregulated in carcinoma in situ and advanced carcinomas. Intriguingly, they are downregulated in invasive fronts. The plastic nature of ESRP expression suggests dual roles for them in cancer progression. Consistently, it has been shown that ESRPs suppress motility and anchorage-independent growth of cancer cells while supporting cell survival by enhancing resistance to reactive oxygen species. Regulatory circuits that fine-tune ESRP gene expression have recently emerged. Here, we summarize recent findings on the molecular mechanisms by which ESRPs exert positive as well as negative effects on cancer progression.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

δEF1:

δ-crystallin enhancer binding protein

EMT:

epithelial-mesenchymal transition

ESRP:

epithelial splicing regulatory protein

FGF:

fibroblast growth factor

FGFR:

fibroblast growth factor receptor

hnRNP:

heterogenous nuclear ribonucleoprotein

HNSCC:

head and neck squamous carcinoma

RRM:

RNA-recognition motif

SIP1:

Smad interacting protein 1.

References

  • Bebee TW, Park JW, Sheridan KI, Warzecha CC, Cieply BW, Rohacek AM, Xing Y, Carstens RP (2015) The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development. eLife 4:e08954

    Article  PubMed Central  Google Scholar 

  • Bhate A, Parker DJ, Bebee TW, Ahn J, Arif W, Rashan EH, Chorghade S, Chau A, Lee JH, Anakk S, Carstens RP, Xiao X, Kalsotra A (2015) ESRP2 controls an adult splicing programme in hepatocytes to support postnatal liver maturation. Nat Commun 6:8768

    Article  PubMed  PubMed Central  Google Scholar 

  • Braunschweig U, Gueroussov S, Plocik AM, Graveley BR, Blencowe BJ (2013) Dynamic integration of splicing within gene regulatory pathways. Cell 152:1252–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, Cheng C (2011) CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest 121:1064–1074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cieply B, Farris J, Denvir J, Ford HL, Frisch SM (2013) Epithelial-mesenchymal transition and tumor suppression are controlled by a reciprocal feedback loop between ZEB1 and Grainyhead-like-2. Cancer Res 73:6299–6309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Comijn J, Berx G, Vermassen P, Verschueren K, van Grunsven L, Bruyneel E, Mareel M, Huylebroeck D, van Roy F (2001) The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell 7:1267–1278

    Article  CAS  PubMed  Google Scholar 

  • David CJ, Manley JL (2010) Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged. Genes Dev 24:2343–2364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dittmar KA, Jiang P, Park JW, Amirikian K, Wan J, Shen S, Xing Y, Carstens RP (2012) Genome-wide determination of a broad ESRP-regulated posttranscriptional network by high-throughput sequencing. Mol Cell Biol 32:1468–1482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, Berx G, Cano A, Beug H, Foisner R (2005) DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene 24:2375–2385

    Article  CAS  PubMed  Google Scholar 

  • Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149

    Article  CAS  PubMed  Google Scholar 

  • Fagoonee S, Bearzi C, Di Cunto F, Clohessy JG, Rizzi R, Reschke M, Tolosano E, Provero P, Pandolfi PP, Silengo L, Altruda F (2013) The RNA binding protein ESRP1 fine-tunes the expression of pluripotency-related factors in mouse embryonic stem cells. PLoS One 8:e72300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiegen D, Haeusler LC, Blumenstein L, Herbrand U, Dvorsky R, Vetter IR, Ahmadian MR (2004) Alternative splicing of Rac1 generates Rac1b, a self-activating GTPase. J Biol Chem 279:4743–4749

    Article  CAS  PubMed  Google Scholar 

  • Horiguchi K, Sakamoto K, Koinuma D, Semba K, Inoue A, Inoue S, Fujii H, Yamaguchi A, Miyazawa K, Miyazono K, Saitoh M (2012) TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP. Oncogene 31:3190–3201

    Article  CAS  PubMed  Google Scholar 

  • Horvath A, Pakala SB, Mudvari P, Reddy SD, Ohshiro K, Casimiro S, Pires R, Fuqua SA, Toi M, Costa L, Nair SS, Sukumar S, Kumar R (2013) Novel insights into breast cancer genetic variance through RNA sequencing. Sci Rep 3:2256

    Article  PubMed  PubMed Central  Google Scholar 

  • Hoshi Y, Endo K, Shirakihara T, Fukagawa A, Miyazawa K, Saitoh M (2016) The potential role of regulator of G-protein signaling 16 in cell motility mediated by δEF1 family proteins. FEBS Lett 590:270–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishii H, Saitoh M, Sakamoto K, Kondo T, Katoh R, Tanaka S, Motizuki M, Masuyama K, Miyazawa K (2014) Epithelial splicing regulatory proteins 1 (ESRP1) and 2 (ESRP2) suppress cancer cell motility via different mechanisms. J Biol Chem 289:27386–27399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H, Oshima M, Ikeda T, Asaba R, Yagi H, Masuko T, Shimizu T, Ishikawa T, Kai K, Takahashi E, Imamura Y, Baba Y, Ohmura M, Suematsu M, Baba H, Saya H (2011) CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19:387–400

    Article  CAS  PubMed  Google Scholar 

  • Jordan P, Brazåo R, Boavida MG, Gespach C, Chastre E (1999) Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene 18:6835–6839

    Article  CAS  PubMed  Google Scholar 

  • Kaida D, Schneider-Poesch T, Yoshida M (2012) Splicing in oncogenesis and tumor suppression. Cancer Sci 103:1611–1616

    Article  CAS  PubMed  Google Scholar 

  • Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leontieva OV, Ionov Y (2009) RNA-binding motif protein 35A is a novel tumor suppressor for colorectal cancer. Cell Cycle 8:490–497

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu H, Liu J, Liu S, Zeng J, Ding D, Carstens RP, Cong Y, Xu X, Guo W (2013) Exo70 isoform switching upon epithelial-mesenchymal transition mediates cancer cell invasion. Dev Cell 27:560–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizutani A, Koinuma D, Seimiya H, Miyazono K (2015) The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma. Oncogene. doi:10.1038/onc2015.412

  • Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  CAS  PubMed  Google Scholar 

  • Preca BT, Bajdak K, Mock K, Sundararajan V, Pfannstiel J, Maurer J, Wellner U, Hopt UT, Brummer T, Brabletz S, Brabletz T, Stemmler MP (2015) A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer 137:2566–2577

    Article  CAS  PubMed  Google Scholar 

  • Reinke LM, Xu Y, Cheng C (2012) Snail represses the splicing regulator epithelial splicing regulatory protein 1 to promote epithelial-mesenchymal transition. J Biol Chem 287:36435–36442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E (2000) Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013–3020

    Article  CAS  PubMed  Google Scholar 

  • Shirakihara T, Horiguchi K, Miyazawa K, Ehata S, Shibata T, Morita I, Miyazono K, Saitoh M (2011) TGF-β regulates isoform switching of FGF receptors and epithelial-mesenchymal transition. EMBO J 30:783–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueda J, Matsuda Y, Yamahatsu K, Uchida E, Naito Z, Korc M, Ishiwata T (2014) Epithelial splicing regulatory protein 1 is a favorable prognostic factor in pancreatic cancer that attenuates pancreatic metastases. Oncogene 33:4485–4495

    Article  CAS  PubMed  Google Scholar 

  • Warzecha CC, Carstens RP (2012) Complex changes in alternatice pre-mRNA splicing play a central role in the epithelial-to-mesenchymal transition (EMT). Semin Cancer Biol 22:417–427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP (2009a) ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Mol Cell 33:591–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warzecha CC, Shen S, Xing Y, Carstens RP (2009b) The epithelial splicing regulatory factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 6:546–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warzecha CC, Jiang P, Amirikian K, Ditmmar KA, Lu H, Shen S, Guo W, Xing Y, Carstens RP (2010) An ESRP-regualted splicing programme is abrogated during the epithelial-mesenchymal transition. EMBO J 29:3286–3300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Werner S, Frey S, Riethdorf S, Schulze C, Alawi M, Kling L, Vafaizadeh V, Sauter G, Terracciano L, Schumacher U, Pantel K, Assmann V (2013) Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer. J Biol Chem 288:22993–23008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiang X, Deng Z, Zhuang X, Ju S, Mu J, Jiang H, Zhang L, Yan J, Miller D, Zhang HG (2012) Grhl2 determines the epithelial phenotype of breast cancers and promotes tumor progression. PLoS One 7:e50781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu Y, Gao XD, Lee JH, Huang H, Tan H, Ahn J, Reinke LM, Peter ME, Feng Y, Gius D, Siziopikou KP, Peng J, Xiao X, Cheng C (2014) Cell type-restricted activity of hnRNPM promotes breast cancer metastasis via regulating alternative splicing. Genes Dev 28:1191–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T, Mogushi K, Tanaka H, Osawa T, Kanki Y, Minami T, Aburatani H, Ohmura M, Kubo A, Suematsu M, Takahashi K, Saya H, Nagano O (2012) Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. Nat Commun 3:883

    Article  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported by the Vehicle Racing Commemorative Foundation and the JSPS Core-to-Core Program ‘Cooperative International Framework in TGF-β Family Signaling’.

Conflict of Interest

None declared

Author information

Authors and Affiliations

  1. Department of Biochemistry, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, 408-3898, Japan

    Akira Hayakawa, Masao Saitoh & Keiji Miyazawa

Authors
  1. Akira Hayakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masao Saitoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keiji Miyazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keiji Miyazawa .

Editor information

Editors and Affiliations

  1. Biochem and Mol Biol, Baylor College of Medicine, Houston, Texas, USA

    M. Zouhair Atassi

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Hayakawa, A., Saitoh, M., Miyazawa, K. (2016). Dual Roles for Epithelial Splicing Regulatory Proteins 1 (ESRP1) and 2 (ESRP2) in Cancer Progression. In: Atassi, M. (eds) Protein Reviews. Advances in Experimental Medicine and Biology(), vol 925. Springer, Singapore. https://doi.org/10.1007/5584_2016_50

Download citation

Publish with us

Policies and ethics

Search

Navigation