CUX1及其分子调控机制在人类恶性肿瘤中的研究进展
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摘要
同源框CUT样蛋白1(CUX1),又称CDP(CCAAT位移蛋白),CUT或CUTL1,是DNA结合蛋白同源域家族的成员。CUX1基因在转录和翻译过程中形成不同长度的蛋白亚型,包括P200、P110和P75。除髓系白血病外,CUX1蛋白被发现在乳腺癌、肺癌、胰腺癌、胶质瘤、胰腺神经内分泌肿瘤等多种癌组织中过表达,在癌旁组织中不表达或低表达,且表达量与肿瘤恶性程度和病人预后相关。因此,CUX1可作为多种恶性肿瘤诊断的新型分子标志物及治疗靶点。在肿瘤中的长期研究中逐渐明晰CUX1的作用机制,解释其癌基因和抑癌基因的矛盾。在机制研究中发现,全长CUX1蛋白可以促进DNA碱基修复,与肿瘤耐药性相关;CUX1短亚型可以通过介导PI3K/AKT,Wnt/β-catenin,TGF-β等信号通路调控肿瘤的增殖、迁移和侵袭过程。本文重点介绍CUX1与肿瘤的相关性及其调控机制的研究进展。
Cut like hemeobox 1 protein(CUX1), also known as CDP、CUT or CUTL1, is a member of homeodomain DNAbinding protein family. In the process of transcription and translation, CUX1 gene can produce different protein isoforms with different lengths, including p200, P110 and p75. The loss of CUX1 plays a positive role in Myeloid Leukemia as reported. On the contrary, CUX1 overexpresses is found in a lot kinds of cancers, such as mammary cancer, lung cancer, pancreatic cancer,glioma and pancreatic neuroendocrine tumor, and its expression level is connected with patients prognosis. So, CUX1 can act as a potential biologic marker and therapeutic target for diagnosis and prognosis of tumors. The paradox role of CUX1 in cancers can be explained with researches after a long time. In the fundamental studies, P200 as an unabridged protein isoform can stimulate DNA base repairing, which is associated with the pharmaceutic resistance of cancer; and the short isoforms of CUX1 can regulate the proliferation, migration and invasion through regulating some signal pathways, such as PI3 k/AKT、Wnt/β-catenin and TGF-β pathways. This review aims to introduce the research progress about correlation analysis and regulatory mechanism of CUX1 in different tumors.
Cut like hemeobox 1 protein(CUX1), also known as CDP、CUT or CUTL1, is a member of homeodomain DNAbinding protein family. In the process of transcription and translation, CUX1 gene can produce different protein isoforms with different lengths, including p200, P110 and p75. The loss of CUX1 plays a positive role in Myeloid Leukemia as reported. On the contrary, CUX1 overexpresses is found in a lot kinds of cancers, such as mammary cancer, lung cancer, pancreatic cancer,glioma and pancreatic neuroendocrine tumor, and its expression level is connected with patients prognosis. So, CUX1 can act as a potential biologic marker and therapeutic target for diagnosis and prognosis of tumors. The paradox role of CUX1 in cancers can be explained with researches after a long time. In the fundamental studies, P200 as an unabridged protein isoform can stimulate DNA base repairing, which is associated with the pharmaceutic resistance of cancer; and the short isoforms of CUX1 can regulate the proliferation, migration and invasion through regulating some signal pathways, such as PI3 k/AKT、Wnt/β-catenin and TGF-β pathways. This review aims to introduce the research progress about correlation analysis and regulatory mechanism of CUX1 in different tumors.
引文
[1]Bray F,Ferlay J,Soerjomataram I,et al.Global Cancer statistics2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2018,68(6):394-424.
[2]陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤,2018,27(1):1-14.
[3]Kedinger V, Nepveu A.The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion[J].Cell Adh Migr,2010,4(3):348-52.
[4]Cubelos B,Sebastian-Serrano A,Beccari L,et al.Cuxl and Cux2regulate dendritic branching,spine morphology,and synapses of the upper layer neurons of the cortex[J],Neuron,2010,66(4):523-35.
[5]Ellis T,Gambardella L,Horcher M,et al.The transcriptional repressor CDP(Cutll)is essential for epithelial cell differentiation of the lung and the hair follicle[J].Genes Dev,2001,15(17):2307-19.
[6]Rong Zeng W, Soucie E, Sung Moon N,et al.Exon/intron structure and alternative transcripts of the CUTL1 gene[J].Gene,2000,241(1):75-85.
[7]Ramdzan ZM,Nepveu A.CUX1,a haploinsufficient tumour suppressor gene overexpressed in advanced cancers[J].Nat Rev Cancer,2014,14(10):673-82.
[8]Kaur S,Ramdzan ZM,Guiot MC,et al.CUX1 stimulates APE1enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide[J].Neuro Oncol,2018,20(4):484-93.
[9]Truscott M,Raynal L,Wang Y, et al.The N-terminal region of the CCAAT displacement protein(CDP)/Cux transcription factor functions as an autoinhibitory domain that modulates DNAbinding[J].J Biol Chem,2004,279(48):49787-94.
[10]Arthur RK,An N,Khan S,et al.The haploinsufficient tumor suppressor,CUX1,acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters[J].Nucleic Acids Res,2017,45(11):6350-61.
[11]Sharma M,Fopma A,Brantley JG,et al.Coexpression of Cux-1and notch signaling pathway components during kidney development[J].Dev Dyn,2004,231(4):828-38.
[12]Sharma M,Brantley JG,Vassmer D,et al.The homeodomain protein Cuxl interacts with Grg4 to repress p27 kip1 expression during kidney development[J].Gene,2009,439(1/2):87-94.
[13]Sinclair AM,Lee JA,Goldstein A,et al.Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice[J].Blood,2001,98(13):3658-67.
[14]Tufarelli C,Fujiwara Y,Zappulla DC,et al.Hair defects and pup loss in mice with targeted deletion of the first cut repeat domain of the Cux/CDP homeoprotein gene[J].Dev Biol,1998,200(1):69-81.
[15]Ramdzan ZM,Vadnais C,Pal R,et al.RAS transformation requires CUX1-dependent repair of oxidative DNA damage[J].PLoS Biol,2014,12(3):e1001807.
[16]Truscott M,Denault JB,Goulet B,et al.Carboxyl-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells[J].J Biol Chem,2007,282(41):30216-26.
[17]Sansregret L,Goulet B,Harada R,et al.The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase[J].Mol Cell Biol,2006,26(6):2441-55.
[18]Kedinger V,Sansregret L,Harada R,et al.p110 CUX1homeodomain protein stimulates cell migration and invasion in part through a regulatory cascade culminating in the repression of ecadherin and occludin[J].J Biol Chem,2009,284(40):27701-11.
[19]Vadnais C,Shooshtarizadeh P,Rajadurai CV,et al.Autocrine activation of the Wnt/β-Catenin pathway by CUX1 and GLIS1 in breast cancers[J].Biol Open,2014,3(10):937-46.
[20]Goulet B,Baruch A,Moon NS,et al.A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor[J].Mol Cell,2004,14(2):207-19.
[21]Moon NS,Premdas P,Truscott M,et al.S phase-specific proteolytic cleavage is required to activate stable DNA binding by the CDP/Cut homeodomain protein[J].Mol Cell Biol,2001,21(18):6332-45.
[22]Goulet B,Watson P,Poirier M,et al.Characterization of a tissuespecific CDP/Cux isoform,p75,activated in breast tumor cells[J].Cancer Res,2002,62(22):6625-33.
[23]Cadieux C,Kedinger V,Yao L,et al.Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types[J].Cancer Res,2009,69(18):7188-97.
[24]Wang J,Wang Y,Sun D,et al.CUTL1 induces epithelialmesenchymal transition in non-small cell lung Cancer[J].Oncol Rep,2017,37(5):3068-74.
[25]Michl P,Ramjaun AR,Pardo OE,et al.CUTL1 is a target of TGF(beta)signaling that enhances Cancer cell motility and invasiveness[J].Cancer Cell,2005,7(6):52 1-32.
[26]Ripka S,Konig A,Buchholz M,et al.WNT5A--target of CUTL1and potent modulator of tumor cell migration and invasion in pancreatic Cancer[J].Carcinogenesis,2007,28(6):1178-87.
[27]Krug S,Kuhnemuth B,Griesmann H,et al.CUX1:a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms[J].Endocr Relat Cancer,2014,21(6):879-90.
[28]Burton LJ,Dougan J,Jones J,et al.Targeting the nuclear cathepsin L CCAAT displacement protein/cut homeobox transcription Factor-Epithelial mesenchymal transition pathway in prostate and breast Cancer cells with the Z-FY-CHO inhibitor[J].Mol Cell Biol,2017,37(5):e00297-16.
[29]Luna-Fineman S,Shannon KM,Atwater SK,et al.Myelodysplastic and myeloproliferative disorders of childhood:a study of 167patients[J].Blood,1999,93(2):459-66.
[30]Bejar R,Levine R,Ebert BL.Unraveling the molecular pathophysiology of myelodysplastic syndromes[J].J Clin Oncol,2011,29(5):504-15.
[31]Patnaik MM,Tefferi A.Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia[J].Blood Cancer J,2016,6(2):e393.
[32]Mcnerney ME,Brown CD,Wang X,et al.CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7frequently inactivated in acute myeloid leukemia[J].Blood,2013,121(6):975-83.
[33]Wong CC,Martincorena L,Rust AG,et al.Inactivating CUX1mutations promote tumorigenesis[J].Nat Genet,2014,46(1):33-8.
[34]An N,Khan S,Imgruet MK,et al.Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS[J].Blood,2018,13 1(24):2682-97.
[35]Cadieux C,Fournier S,Peterson AC,et al.Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia[J].Cancer Res,2006,66(19):9492-501.
[36]Zeng WR,Watson P,Lin J,et al.Refined mapping of the region of loss of heterozygosity on the long arm of chromosome 7 in human breast Cancer defines the location of a second tumor suppressor gene at 7q22 in the region of the CUTL1 gene[J].Oncogene,1999,18(11):2015-21.
[37]Wilson BJ,Harada R,Leduy L,et al.CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2(PAR2)J][J].J Biol Cher,2009,284(1):36-45.
[38]Burton LJ,Henderson V,Liburd L,et al.Snail transcription factor NLS and importin(31 regulate the subcellular localization of Cathepsin L and Cux1[J].Biochem Biophys Res Commun,2017,491(1):59-64.
[39]Chen J,Zhou Z,Yao Y,et al.Dipalmitoylphosphatidic acid inhibits breast Cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway[J].J Cell Mol Med,2018,22(10):4760-70.
[40]Wang L,Zhao Y,Xiong Y,et al.K-ras mutation promotes ionizing radiation-induced invasion and migration of lung Cancer in part via the Cathepsin L/CUX1 pathway[J].Exp Cell Res,2018,362(2):424-3 5.
[41]Ripka S,Neesse A,Riedel J,et al.CUX1:target of Akt signalling and mediator of resistance to apoptosis in pancreatic Cancer[J].Gut,2010,59(8):1101-10.
[42]Ripka S,Riedel J,Neesse A,et al.Glutamate receptor GRIA3-target of CUX1 and mediator of tumor progression in pancreatic Cancer[J].Neoplasia,2010,12(8):659-67.
[43]Griesmann H,Ripka S,Pralle M,et al.WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic Cancer[J].Neoplasia,2013,15(1):11-22.
[44]Kuhnemuth B,Muhlberg L,Schipper M,et al.CUX1 modulatespolarization of tumor-associated macrophages by antagonizing NF-κB signaling[J].Oncogene,2015,34(2):177-87.
[45]Fei Y, Xiong Y,Shen X,et al.Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3p/CUXl pathway[J].Cell Signal,2018,44(4);62-71.
[46]Fei Y, Xiong Y,Shen X,et al.Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3p/CUXl pathway[J].Cell Signal,2018,44(4);62-71.
[47]樊星.转录因子CUTL1在恶性黑素瘤发生发展中的作用及机制研究[D].上海:第二军医大学,2011.
[48]王红红.转录因子CUTL1在胃癌多药耐药中的作用及机制研究[D].西安:第四军医大学,2012.
[2]陈万青,孙可欣,郑荣寿,等.2014年中国分地区恶性肿瘤发病和死亡分析[J].中国肿瘤,2018,27(1):1-14.
[3]Kedinger V, Nepveu A.The roles of CUX1 homeodomain proteins in the establishment of a transcriptional program required for cell migration and invasion[J].Cell Adh Migr,2010,4(3):348-52.
[4]Cubelos B,Sebastian-Serrano A,Beccari L,et al.Cuxl and Cux2regulate dendritic branching,spine morphology,and synapses of the upper layer neurons of the cortex[J],Neuron,2010,66(4):523-35.
[5]Ellis T,Gambardella L,Horcher M,et al.The transcriptional repressor CDP(Cutll)is essential for epithelial cell differentiation of the lung and the hair follicle[J].Genes Dev,2001,15(17):2307-19.
[6]Rong Zeng W, Soucie E, Sung Moon N,et al.Exon/intron structure and alternative transcripts of the CUTL1 gene[J].Gene,2000,241(1):75-85.
[7]Ramdzan ZM,Nepveu A.CUX1,a haploinsufficient tumour suppressor gene overexpressed in advanced cancers[J].Nat Rev Cancer,2014,14(10):673-82.
[8]Kaur S,Ramdzan ZM,Guiot MC,et al.CUX1 stimulates APE1enzymatic activity and increases the resistance of glioblastoma cells to the mono-alkylating agent temozolomide[J].Neuro Oncol,2018,20(4):484-93.
[9]Truscott M,Raynal L,Wang Y, et al.The N-terminal region of the CCAAT displacement protein(CDP)/Cux transcription factor functions as an autoinhibitory domain that modulates DNAbinding[J].J Biol Chem,2004,279(48):49787-94.
[10]Arthur RK,An N,Khan S,et al.The haploinsufficient tumor suppressor,CUX1,acts as an analog transcriptional regulator that controls target genes through distal enhancers that loop to target promoters[J].Nucleic Acids Res,2017,45(11):6350-61.
[11]Sharma M,Fopma A,Brantley JG,et al.Coexpression of Cux-1and notch signaling pathway components during kidney development[J].Dev Dyn,2004,231(4):828-38.
[12]Sharma M,Brantley JG,Vassmer D,et al.The homeodomain protein Cuxl interacts with Grg4 to repress p27 kip1 expression during kidney development[J].Gene,2009,439(1/2):87-94.
[13]Sinclair AM,Lee JA,Goldstein A,et al.Lymphoid apoptosis and myeloid hyperplasia in CCAAT displacement protein mutant mice[J].Blood,2001,98(13):3658-67.
[14]Tufarelli C,Fujiwara Y,Zappulla DC,et al.Hair defects and pup loss in mice with targeted deletion of the first cut repeat domain of the Cux/CDP homeoprotein gene[J].Dev Biol,1998,200(1):69-81.
[15]Ramdzan ZM,Vadnais C,Pal R,et al.RAS transformation requires CUX1-dependent repair of oxidative DNA damage[J].PLoS Biol,2014,12(3):e1001807.
[16]Truscott M,Denault JB,Goulet B,et al.Carboxyl-terminal proteolytic processing of CUX1 by a caspase enables transcriptional activation in proliferating cells[J].J Biol Chem,2007,282(41):30216-26.
[17]Sansregret L,Goulet B,Harada R,et al.The p110 isoform of the CDP/Cux transcription factor accelerates entry into S phase[J].Mol Cell Biol,2006,26(6):2441-55.
[18]Kedinger V,Sansregret L,Harada R,et al.p110 CUX1homeodomain protein stimulates cell migration and invasion in part through a regulatory cascade culminating in the repression of ecadherin and occludin[J].J Biol Chem,2009,284(40):27701-11.
[19]Vadnais C,Shooshtarizadeh P,Rajadurai CV,et al.Autocrine activation of the Wnt/β-Catenin pathway by CUX1 and GLIS1 in breast cancers[J].Biol Open,2014,3(10):937-46.
[20]Goulet B,Baruch A,Moon NS,et al.A cathepsin L isoform that is devoid of a signal peptide localizes to the nucleus in S phase and processes the CDP/Cux transcription factor[J].Mol Cell,2004,14(2):207-19.
[21]Moon NS,Premdas P,Truscott M,et al.S phase-specific proteolytic cleavage is required to activate stable DNA binding by the CDP/Cut homeodomain protein[J].Mol Cell Biol,2001,21(18):6332-45.
[22]Goulet B,Watson P,Poirier M,et al.Characterization of a tissuespecific CDP/Cux isoform,p75,activated in breast tumor cells[J].Cancer Res,2002,62(22):6625-33.
[23]Cadieux C,Kedinger V,Yao L,et al.Mouse mammary tumor virus p75 and p110 CUX1 transgenic mice develop mammary tumors of various histologic types[J].Cancer Res,2009,69(18):7188-97.
[24]Wang J,Wang Y,Sun D,et al.CUTL1 induces epithelialmesenchymal transition in non-small cell lung Cancer[J].Oncol Rep,2017,37(5):3068-74.
[25]Michl P,Ramjaun AR,Pardo OE,et al.CUTL1 is a target of TGF(beta)signaling that enhances Cancer cell motility and invasiveness[J].Cancer Cell,2005,7(6):52 1-32.
[26]Ripka S,Konig A,Buchholz M,et al.WNT5A--target of CUTL1and potent modulator of tumor cell migration and invasion in pancreatic Cancer[J].Carcinogenesis,2007,28(6):1178-87.
[27]Krug S,Kuhnemuth B,Griesmann H,et al.CUX1:a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms[J].Endocr Relat Cancer,2014,21(6):879-90.
[28]Burton LJ,Dougan J,Jones J,et al.Targeting the nuclear cathepsin L CCAAT displacement protein/cut homeobox transcription Factor-Epithelial mesenchymal transition pathway in prostate and breast Cancer cells with the Z-FY-CHO inhibitor[J].Mol Cell Biol,2017,37(5):e00297-16.
[29]Luna-Fineman S,Shannon KM,Atwater SK,et al.Myelodysplastic and myeloproliferative disorders of childhood:a study of 167patients[J].Blood,1999,93(2):459-66.
[30]Bejar R,Levine R,Ebert BL.Unraveling the molecular pathophysiology of myelodysplastic syndromes[J].J Clin Oncol,2011,29(5):504-15.
[31]Patnaik MM,Tefferi A.Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia[J].Blood Cancer J,2016,6(2):e393.
[32]Mcnerney ME,Brown CD,Wang X,et al.CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7frequently inactivated in acute myeloid leukemia[J].Blood,2013,121(6):975-83.
[33]Wong CC,Martincorena L,Rust AG,et al.Inactivating CUX1mutations promote tumorigenesis[J].Nat Genet,2014,46(1):33-8.
[34]An N,Khan S,Imgruet MK,et al.Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS[J].Blood,2018,13 1(24):2682-97.
[35]Cadieux C,Fournier S,Peterson AC,et al.Transgenic mice expressing the p75 CCAAT-displacement protein/Cut homeobox isoform develop a myeloproliferative disease-like myeloid leukemia[J].Cancer Res,2006,66(19):9492-501.
[36]Zeng WR,Watson P,Lin J,et al.Refined mapping of the region of loss of heterozygosity on the long arm of chromosome 7 in human breast Cancer defines the location of a second tumor suppressor gene at 7q22 in the region of the CUTL1 gene[J].Oncogene,1999,18(11):2015-21.
[37]Wilson BJ,Harada R,Leduy L,et al.CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2(PAR2)J][J].J Biol Cher,2009,284(1):36-45.
[38]Burton LJ,Henderson V,Liburd L,et al.Snail transcription factor NLS and importin(31 regulate the subcellular localization of Cathepsin L and Cux1[J].Biochem Biophys Res Commun,2017,491(1):59-64.
[39]Chen J,Zhou Z,Yao Y,et al.Dipalmitoylphosphatidic acid inhibits breast Cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway[J].J Cell Mol Med,2018,22(10):4760-70.
[40]Wang L,Zhao Y,Xiong Y,et al.K-ras mutation promotes ionizing radiation-induced invasion and migration of lung Cancer in part via the Cathepsin L/CUX1 pathway[J].Exp Cell Res,2018,362(2):424-3 5.
[41]Ripka S,Neesse A,Riedel J,et al.CUX1:target of Akt signalling and mediator of resistance to apoptosis in pancreatic Cancer[J].Gut,2010,59(8):1101-10.
[42]Ripka S,Riedel J,Neesse A,et al.Glutamate receptor GRIA3-target of CUX1 and mediator of tumor progression in pancreatic Cancer[J].Neoplasia,2010,12(8):659-67.
[43]Griesmann H,Ripka S,Pralle M,et al.WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic Cancer[J].Neoplasia,2013,15(1):11-22.
[44]Kuhnemuth B,Muhlberg L,Schipper M,et al.CUX1 modulatespolarization of tumor-associated macrophages by antagonizing NF-κB signaling[J].Oncogene,2015,34(2):177-87.
[45]Fei Y, Xiong Y,Shen X,et al.Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3p/CUXl pathway[J].Cell Signal,2018,44(4);62-71.
[46]Fei Y, Xiong Y,Shen X,et al.Cathepsin L promotes ionizing radiation-induced U251 glioma cell migration and invasion through regulating the GSK-3p/CUXl pathway[J].Cell Signal,2018,44(4);62-71.
[47]樊星.转录因子CUTL1在恶性黑素瘤发生发展中的作用及机制研究[D].上海:第二军医大学,2011.
[48]王红红.转录因子CUTL1在胃癌多药耐药中的作用及机制研究[D].西安:第四军医大学,2012.