Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription

Kohji Yamada, Mutsumi Hayashi, Hiroko Madokoro, Hiroko Nishida, Wenlin Du, Kei Ohnuma, Michiie Sakamoto, Chikao Morimoto, Taketo Yamada

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus.

Original languageEnglish
Article numbere62304
JournalPLoS One
Volume8
Issue number4
DOIs
Publication statusPublished - 2013 Apr 29

Fingerprint

Neoplasm Antibodies
Antibodies, Monoclonal, Humanized
Cell growth
Transcription
Tumors
cell growth
monoclonal antibodies
transcription (genetics)
neoplasms
Growth
Genes
Cells
Neoplasms
endocytosis
Monoclonal Antibodies
Caveolins
Dipeptidyl Peptidase 4
RNA Polymerase II
Cell proliferation
Endocytosis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription. / Yamada, Kohji; Hayashi, Mutsumi; Madokoro, Hiroko; Nishida, Hiroko; Du, Wenlin; Ohnuma, Kei; Sakamoto, Michiie; Morimoto, Chikao; Yamada, Taketo.

In: PLoS One, Vol. 8, No. 4, e62304, 29.04.2013.

Research output: Contribution to journalArticle

Yamada, Kohji ; Hayashi, Mutsumi ; Madokoro, Hiroko ; Nishida, Hiroko ; Du, Wenlin ; Ohnuma, Kei ; Sakamoto, Michiie ; Morimoto, Chikao ; Yamada, Taketo. / Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription. In: PLoS One. 2013 ; Vol. 8, No. 4.
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AU - Hayashi, Mutsumi

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AU - Nishida, Hiroko

AU - Du, Wenlin

AU - Ohnuma, Kei

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AU - Morimoto, Chikao

AU - Yamada, Taketo

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AB - CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus.

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