RESEARCH ARTICLE

Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells

  • Dengwen Li 1 ,
  • Xiaodong Sun 1 ,
  • Linlin Zhang 1 ,
  • Bing Yan 1 ,
  • Songbo Xie 1 ,
  • Ruming Liu 1 ,
  • Min Liu , 2 ,
  • Jun Zhou , 1
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  • 1. Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
  • 2. Department of Biochemistry, Basic Medical College, Tianjin Medical University, Tianjin 300070, China

Received date: 17 Oct 2013

Accepted date: 05 Nov 2013

Published date: 23 Jun 2014

Copyright

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy.

Cite this article

Dengwen Li , Xiaodong Sun , Linlin Zhang , Bing Yan , Songbo Xie , Ruming Liu , Min Liu , Jun Zhou . Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells[J]. Protein & Cell, 2014 , 5(3) : 214 -223 . DOI: 10.1007/s13238-013-0010-3

1
Aldana-Masangkay GI, Sakamoto KM (2011) The role of HDAC6 in cancer. J Biomed Biotechnol2011: 875824

DOI

2
Amos LA, Schlieper D (2005) Microtubules and maps. Adv Protein Chem71: 257-298

DOI

3
Berridge MV, Herst PM, Tan AS (2005) Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Annu<?Pub Caret?> Rev11: 127-152

DOI

4
Dallavalle S, Pisano C, Zunino F (2012) Development and therapeutic impact of HDAC6-selective inhibitors. Biochem Pharmacol84: 756-765

DOI

5
Dragestein KA, van Cappellen WA, van Haren J, Tsibidis GD, Akhmanova A, Knoch TA, Grosveld F, Galjart N (2008) Dynamic behavior of GFP-CLIP-170 reveals fast protein turnover on microtubule plus ends. J Cell Biol180: 729-737

DOI

6
Etienne-Manneville S (2008) Polarity proteins in migration and invasion. Oncogene27: 6970-6980

DOI

7
Ghaneh P, Costello E, Neoptolemos JP (2008) Biology and management of pancreatic cancer. Postgrad Med J84: 478-497

DOI

8
Haggarty SJ, Koeller KM, Wong JC, Grozinger CM, Schreiber SL (2003) Domain-selective small-molecule inhibitor of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation. Proc Natl Acad Sci USA100: 4389-4394

DOI

9
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev20: 1218-1249

DOI

10
Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, Yoshida M, Wang XF, Yao TP (2002) HDAC6 is a microtubuleassociated deacetylase. Nature417: 455-458

DOI

11
Huo L, Li D, Sun X, Shi X, Karna P, Yang W, Liu M, Qiao W, Aneja R, Zhou J (2011) Regulation of Tat acetylation and transactivation activity by the microtubule-associated deacetylase HDAC6. J Biol Chem286: 9280-9286

DOI

12
Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP (2005) HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell18: 601-607

DOI

13
Li H, Liu XS, Yang X, Wang Y, Turner JR, Liu X (2010) Phosphorylation of CLIP-170 by Plk1 and CK2 promotes timely formation of kinetochore-microtubule attachments. EMBO J29: 2953-2965

DOI

14
Li D, Xie S, Ren Y, Huo L, Gao J, Cui D, Liu M, Zhou J (2011) Microtubule-associated deacetylase HDAC6 promotes angiogenesis by regulating cell migration in an EB1-dependent manner. Protein Cell2: 150-160

DOI

15
Lindemann RK, Gabrielli B, Johnstone RW (2004) Histone-deacetylase inhibitors for the treatment of cancer. Cell Cycle3: 779-788

DOI

16
Maekawa H, Schiebel E (2004) CLIP-170 family members: a motordriven ride to microtubule plus ends. Dev Cell6: 746-748

DOI

17
Matsuyama A, Shimazu T, Sumida Y, Saito A, Yoshimatsu Y, Seigneurin-Berny D, Osada H, Komatsu Y, Nishino N, Khochbin S (2002) In vivo destabilization of dynamic microtubules by HDAC6-mediated deacetylation. EMBO J21: 6820-6831

DOI

18
Nakano A, Kato H, Watanabe T, Min KD, Yamazaki S, Asano Y, Seguchi O, Higo S, Shintani Y, Asanuma H (2010) AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nat Cell Biol12: 583-590

DOI

19
Olson MF, Sahai E (2009) The actin cytoskeleton in cancer cell motility. Clin Exp Metastasis26: 273-287

DOI

20
Parmigiani RB, Xu WS, Venta-Perez G, Erdjument-Bromage H, Yaneva M, Tempst P, Marks PA (2008) HDAC6 is a specific deacetylase of peroxiredoxins and is involved in redox regulation. Proc Natl Acad Sci USA105: 9633-9638

DOI

21
Pierre P, Scheel J, Rickard JE, Kreis TE (1992) CLIP-170 links endocytic vesicles to microtubules. Cell70: 887-900

DOI

22
Rodriguez OC, Schaefer AW, Mandato CA, Forscher P, Bement WM, Waterman-Storer CM (2003) Conserved microtubule-actin interactions in cell movement and morphogenesis. Nat Cell Biol5: 599-609

DOI

23
Shi X, Liu M, Li D, Wang J, Aneja R, Zhou J (2012) Cep70 contributes to angiogenesis by modulating microtubule rearrangement and stimulating cell polarization and migration. Cell Cycle11: 1554-1563

DOI

24
Sun X, Li D, Yang Y, Ren Y, Li J, Wang Z, Dong B, Liu M, Zhou J (2012) Microtubule-binding protein CLIP-170 is a mediator of paclitaxel sensitivity. J Pathol226: 666-673

DOI

25
Sun X, Li F, Dong B, Suo S, Liu M, Li D, Zhou J (2013a) Regulation of tumor angiogenesis by the microtubule-binding protein CLIP-170. Protein Cell4: 266-276

DOI

26
Sun X, Liu M, Hao J, Li D, Luo Y, Wang X, Yang Y, Li F, Shui W, Chen Q (2013b) Parkin deficiency contributes to pancreatic tumorigenesis by inducing spindle multipolarity and misorientation. Cell Cycle12: 1133-1141

DOI

27
Takashima S (2011) AMP-kinase regulates the speed of microtubule polymerization and cell polarity by phosphorylation of microtubule plus end protein CLIP-170. Seikagaku J Jpn Biochem Soc83: 850-854

28
Valenzuela-Fernandez A, Cabrero JR, Serrador JM, Sanchez-Madrid F (2008) HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends Cell Biol18: 291-297

DOI

29
Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc1: 1112-1116

DOI

30
Waterman-Storer CM, Salmon E (1999) Positive feedback interactions between microtubule and actin dynamics during cell motility. Curr Opin Cell Biol11: 61-67

DOI

31
Wells A, Grahovac J, Wheeler S, Ma B, Lauffenburger D (2013) Targeting tumor cell motility as a strategy against invasion and metastasis. Trends Pharmacol Sci34: 283-289

DOI

32
Yang X, Li H, Liu XS, Deng A, Liu X (2009) Cdc2-mediated phosphorylation of CLIP-170 is essential for its inhibition of centrosome reduplication. J Biol Chem284: 28775-28782

DOI

33
Zhang Y, Li N, Caron C, Matthias G, Hess D, Khochbin S, Matthias P (2003) HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J22: 1168-1179

DOI

34
Zhang X, Yuan Z, Zhang Y, Yong S, Salas-Burgos A, Koomen J, Olashaw N, Parsons JT, Yang XJ, Dent SR (2007) HDAC6 modulates cell motility by altering the acetylation level of cortactin. Mol Cell27: 197-213

DOI

35
Zhou J, Vos CC, Gjyrezi A, Yoshida M, Khuri FR, Tamanoi F, Giannakakou P (2009) The protein farnesyl transferase regulates HDAC6 activity in a microtubule-dependent manner. J Biol Chem284: 9648-9655

DOI

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