过表达组蛋白去乙酰基酶11抑制基底样乳腺癌细胞的侵袭和转移（英文）
|
摘要
目的研究组蛋白去乙酰基酶11(HDAC11)在基底样乳腺癌(BLBC)细胞侵袭和转移中的调控作用。方法利用GEO和TCGA数据库分析了HDAC11在BLBC中的表达,并用Transwell实验和裸鼠模型研究HDAC11对BLBC细胞侵袭和转移的影响。使用免疫共沉淀的方法观察HDAC11与Twist蛋白的相互结合,用启动子报告基因和染色体免疫共沉淀的方法鉴定HAS2是否为Twist的靶基因。结果与其他乳腺癌亚型相比,HDAC11在基底样乳腺癌中的表达较低。在BLBC细胞中过表达HDAC11可以强烈抑制BLBC细胞的体外迁移、侵袭和在裸鼠体内转移。HDAC11识别并占据Twist蛋白的DNA结合域,对抗其促侵袭的功能,并抑制Twist诱导的HAS2基因转录。结论 HDAC11过表达可抑制BLBC细胞的侵袭和转移。
Objective Histone deacetylase 11(HDAC11) is a class IV member of histone deacetylase family, and its role in regulating cancer cell invasion and metastasis remains unclear. We aimed to investigate the role of HDAC11 in regulating the biological behaviors of basal-like breast cancer(BLBC) cells. Methods We analyzed the expression of HDAC11 based on Gene Expression Omnibus(GEO) and the Cancer Genome Atlas(TCGA). The effects of HDAC11 on the cell invasion and metastasis were examined using Transwell assay and in amousemodel. The interaction between HDAC11 and Twist was detected with immunoprecipitation.We identified HAS2 as a target gene of Twist using promoter luciferase assay and chromatin immunoprecipitation assay. Results HDAC11 was lowly expressed in BLBC cells.HDAC11 overexpression suppressed BLBC cell invasion in vitro and theirmetastasis in nude mice. Mechanistically, HDAC11 directly interacted with Twist protein, antagonized its pro-invasive function and repressed Twist-induced HAS2 gene transcription. Conclusion Our data suggest that HDAC11 acts as a negative modulator of invasion and metastasis of BLBC cells.
Objective Histone deacetylase 11(HDAC11) is a class IV member of histone deacetylase family, and its role in regulating cancer cell invasion and metastasis remains unclear. We aimed to investigate the role of HDAC11 in regulating the biological behaviors of basal-like breast cancer(BLBC) cells. Methods We analyzed the expression of HDAC11 based on Gene Expression Omnibus(GEO) and the Cancer Genome Atlas(TCGA). The effects of HDAC11 on the cell invasion and metastasis were examined using Transwell assay and in amousemodel. The interaction between HDAC11 and Twist was detected with immunoprecipitation.We identified HAS2 as a target gene of Twist using promoter luciferase assay and chromatin immunoprecipitation assay. Results HDAC11 was lowly expressed in BLBC cells.HDAC11 overexpression suppressed BLBC cell invasion in vitro and theirmetastasis in nude mice. Mechanistically, HDAC11 directly interacted with Twist protein, antagonized its pro-invasive function and repressed Twist-induced HAS2 gene transcription. Conclusion Our data suggest that HDAC11 acts as a negative modulator of invasion and metastasis of BLBC cells.
引文
[1]Rakha EA,El-Sayed ME,Reis-Filho J,et al.Patho-biological aspects of basal-like breast cancer[J].Breast Cancer Res Treat,2009,1 13(3):411-22.
[2]Denkert C,Liedtke C,Tutt A,et al.Molecular alterations in triplenegative breast cancer-the road to new treatment strategies[J].Lancet,2017,389(10087):2430-42.
[3]Gao L,Cueto MA,Asselbergs F,et al.Cloning and functional characterization of HD AC 11,a novel member of the human histone deacetylase family[J].J Biol Chem,2002,277(28):25748-55.
[4]Villagra A,Cheng F,Wang HW,et al.The histone deacetylase HD AC 11 regulates the expression of interleukin 10 and immune tolerance[J].Nat Immunol,2009,10(1):92-100.
[5]Joshi P,Greco TM,Guise AJ,et al.The functional interactome landscape of the human histone deacetylase family[J].Mol Syst Biol,2003,9:672.
[6]Buglio D,Khaskhely NM,Voo KS,et al.HDAC11 plays an essential role in regulating 0X40 ligand expression in Hodgkin lymphoma[J].Blood,2011,117(10):2910-7.
[7]Glozak MA,Seto E,Acetylation/deacetylation modulates the stability of DNA replication licensing factor Cdt1[J].J Biol Chem,2009,284(17):11446-53.
[8]Feng W,Lu Z,Luo RZ,et al.Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer[J].Int J Cancer,2007,120(8):1664-8.
[9]Lozada EM,Andrysik Z,Yin M,et al.Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer[J].Oncotarget,2016,7(15):20425-39.
[10]Moreno-Yruela C,Galleano I,Madsen AS,et al.Histone deacetylase11 is an epsilon-N-myristoyllysine hydrolase[J].Cell Chem Biol,2018,25(7):849-56,e848.
[11]Kutil Z,Novakova Z,Meleshin M,et al.Histone deacetylase 11 is a fatty-acid deacylase[J].ACS Chem Biol,2018,13(3):685-93.
[12]Thole TM,Lodrini M,Fabian J,et al.Neuroblastoma cells depend on HD AC 11 for mitotic cell cycle progression and survival[J].Cell Death Dis,2017,8(3):e2635.
[13]Wang W,Fu L,Li S,et al.Histone deacetylase 11 suppresses p53expression in pituitary tumor cells[J].Cell Biol Int,2017,41(12):1290-5.
[14]Dai W,Zeller C,Masrour N,et al.Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in highgrade serous ovarian cancer[J].Clin Cancer Res,2013,19(20):5788-97.
[15]Shi J,Wang Y,Zeng L,et al.Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer[J].Cancer Cell,2014,25(2):210-25.
[16]Yang J,Mani SA,Donaher JL,et al.Twist,a master regulator of morphogenesis,plays an essential role in tumor metastasis[J].Cell,2004,117(7):927-39.
[17]Qin Q,Xu Y,He T,et al.Normal and disease-related biological functions of Twist 1 and underlying molecular mechanisms[J].Cell Res,2012,22(1):90-106.
[18]Yang MH,Hsu DS,Wang HW,et al.Bmil is essential in Twistlinduced epithelial-mesenchymal transition[J].Nat Cell Biol,2010,12(10):982-92.
[19]Eckert MA,Lwin TM,Chang AT,et al.Twistl-induced invadopodia formation promotes tumor metastasis[J].Cancer Cell,2011,19(3):372-86.
[20]Yang MH,Wu MZ,Chiou SH,et al.Direct regulation of TWIST by HIF-lalpha promotes metastasis[J].Nat Cell Biol,2008,10(3):295-305.
[21]Sandmann T,Girardot C,Brehme M,et al.A core transcriptional network for early mesoderm development in drosophila melanogaster[J].Genes Dev,2007,21(4):436-49.
[22]Itano N,Kimata K,Mammalian hyaluronan synthases[J].IUBMB Life,2002,54(4):195-9.
[23]Moustakas A,Heldin P,TGFbeta and matrix-regulated epithelial to mesenchymal transition[J].Biochim Biophys Acta,2014,1840(8):2621-34.
[24]Udabage L,Brownlee GR,Waltham M,et al.Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer[J].Cancer Res,2005,65(14):6139-50.
[25]Li Y,Li L,Brown TJ,et al.Silencing of hyaluronan synthase 2suppresses the malignant phenotype of invasive breast cancer cells[J].Int J Cancer,2007,120(12):2557-67.
[26]Bernert B,Porsch H,Heldin P.Hyaluronan synthase 2(HAS2)promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1(TIMP-1)[J].J Biol Chem,2011,286(49):42349-59.
[27]Porsch H,Bernert B,Mehic M,et al.Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2[J].Oncogene,2013,32(37):4355-65.
[2]Denkert C,Liedtke C,Tutt A,et al.Molecular alterations in triplenegative breast cancer-the road to new treatment strategies[J].Lancet,2017,389(10087):2430-42.
[3]Gao L,Cueto MA,Asselbergs F,et al.Cloning and functional characterization of HD AC 11,a novel member of the human histone deacetylase family[J].J Biol Chem,2002,277(28):25748-55.
[4]Villagra A,Cheng F,Wang HW,et al.The histone deacetylase HD AC 11 regulates the expression of interleukin 10 and immune tolerance[J].Nat Immunol,2009,10(1):92-100.
[5]Joshi P,Greco TM,Guise AJ,et al.The functional interactome landscape of the human histone deacetylase family[J].Mol Syst Biol,2003,9:672.
[6]Buglio D,Khaskhely NM,Voo KS,et al.HDAC11 plays an essential role in regulating 0X40 ligand expression in Hodgkin lymphoma[J].Blood,2011,117(10):2910-7.
[7]Glozak MA,Seto E,Acetylation/deacetylation modulates the stability of DNA replication licensing factor Cdt1[J].J Biol Chem,2009,284(17):11446-53.
[8]Feng W,Lu Z,Luo RZ,et al.Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer[J].Int J Cancer,2007,120(8):1664-8.
[9]Lozada EM,Andrysik Z,Yin M,et al.Acetylation and deacetylation of Cdc25A constitutes a novel mechanism for modulating Cdc25A functions with implications for cancer[J].Oncotarget,2016,7(15):20425-39.
[10]Moreno-Yruela C,Galleano I,Madsen AS,et al.Histone deacetylase11 is an epsilon-N-myristoyllysine hydrolase[J].Cell Chem Biol,2018,25(7):849-56,e848.
[11]Kutil Z,Novakova Z,Meleshin M,et al.Histone deacetylase 11 is a fatty-acid deacylase[J].ACS Chem Biol,2018,13(3):685-93.
[12]Thole TM,Lodrini M,Fabian J,et al.Neuroblastoma cells depend on HD AC 11 for mitotic cell cycle progression and survival[J].Cell Death Dis,2017,8(3):e2635.
[13]Wang W,Fu L,Li S,et al.Histone deacetylase 11 suppresses p53expression in pituitary tumor cells[J].Cell Biol Int,2017,41(12):1290-5.
[14]Dai W,Zeller C,Masrour N,et al.Promoter CpG island methylation of genes in key cancer pathways associates with clinical outcome in highgrade serous ovarian cancer[J].Clin Cancer Res,2013,19(20):5788-97.
[15]Shi J,Wang Y,Zeng L,et al.Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer[J].Cancer Cell,2014,25(2):210-25.
[16]Yang J,Mani SA,Donaher JL,et al.Twist,a master regulator of morphogenesis,plays an essential role in tumor metastasis[J].Cell,2004,117(7):927-39.
[17]Qin Q,Xu Y,He T,et al.Normal and disease-related biological functions of Twist 1 and underlying molecular mechanisms[J].Cell Res,2012,22(1):90-106.
[18]Yang MH,Hsu DS,Wang HW,et al.Bmil is essential in Twistlinduced epithelial-mesenchymal transition[J].Nat Cell Biol,2010,12(10):982-92.
[19]Eckert MA,Lwin TM,Chang AT,et al.Twistl-induced invadopodia formation promotes tumor metastasis[J].Cancer Cell,2011,19(3):372-86.
[20]Yang MH,Wu MZ,Chiou SH,et al.Direct regulation of TWIST by HIF-lalpha promotes metastasis[J].Nat Cell Biol,2008,10(3):295-305.
[21]Sandmann T,Girardot C,Brehme M,et al.A core transcriptional network for early mesoderm development in drosophila melanogaster[J].Genes Dev,2007,21(4):436-49.
[22]Itano N,Kimata K,Mammalian hyaluronan synthases[J].IUBMB Life,2002,54(4):195-9.
[23]Moustakas A,Heldin P,TGFbeta and matrix-regulated epithelial to mesenchymal transition[J].Biochim Biophys Acta,2014,1840(8):2621-34.
[24]Udabage L,Brownlee GR,Waltham M,et al.Antisense-mediated suppression of hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer[J].Cancer Res,2005,65(14):6139-50.
[25]Li Y,Li L,Brown TJ,et al.Silencing of hyaluronan synthase 2suppresses the malignant phenotype of invasive breast cancer cells[J].Int J Cancer,2007,120(12):2557-67.
[26]Bernert B,Porsch H,Heldin P.Hyaluronan synthase 2(HAS2)promotes breast cancer cell invasion by suppression of tissue metalloproteinase inhibitor 1(TIMP-1)[J].J Biol Chem,2011,286(49):42349-59.
[27]Porsch H,Bernert B,Mehic M,et al.Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2[J].Oncogene,2013,32(37):4355-65.