Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription

Our plain-English summary of Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription, by K. Yamada, M. Hayashi, H. Madokoro, et al (PloS One, 2013).

The study

• Authors: K. Yamada, M. Hayashi, H. Madokoro, H. Nishida, W. Du, K. Ohnuma, M. Sakamoto, C. Morimoto, T. Yamada
• Journal: PloS One
• Published: 2013;8(4):e62304
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of cultured cancer cells and mice. It did not study asbestos exposure. The authors, in Japan, examined how YS110, a humanized antibody against a protein called CD26, slows the growth of malignant mesothelioma cells. In a mesothelioma cell line, YS110 entered the cells and reached the nucleus within 30 minutes to 2 hours. It also increased the amount of CD26 in the nucleus, which peaked at 2 hours. This entry depended on a cell uptake route involving a protein called caveolin. CD26 was also found in the nucleus of tumors from two mesothelioma patients. In mice, the antibody reached tumor-cell nuclei when injected directly into the tumors. In the nucleus, CD26 attached to a DNA stretch near the POLR2A gene, which makes the largest part of RNA polymerase II, an enzyme the cell needs to read most of its protein-coding genes. YS110 treatment lowered POLR2A levels. Blocking CD26 from entering the nucleus prevented this drop. Lowering POLR2A levels by RNA interference slowed mesothelioma cell growth. The authors concluded that YS110-induced nuclear CD26 represses POLR2A and suppresses cancer cell growth.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experiments on cultured cancer cell lines, a mouse xenograft model (human tumor cells grown in mice), and autopsy tumor specimens
• Who was studied: Malignant mesothelioma cell lines (JMN, MSTO and CD26-expressing MSTO clones), plus T cell leukemia (Jurkat), hepatocellular carcinoma, HEK293 and HeLa cell lines. Also NOG mice carrying JMN or MSTO tumors (3 mice per treatment group) and autopsy tumors from malignant mesothelioma patients (two patients for the CD26 fractionation analysis)
• Exposure: Treatment with the humanized anti-CD26 monoclonal antibody YS110 (and the murine anti-CD26 antibody 1F7), compared with control antibodies. No asbestos exposure was studied.
• Main results:
  • In JMN mesothelioma cells, labeled YS110 appeared in the nucleus as dots, as well as in the cytoplasm, from 30 minutes to 2 hours after treatment
  • In JMN cells, YS110 treatment increased CD26 in the nuclear fraction, peaking at 2 hours and returning close to the original level by 4 hours
  • CD26 was found in the nuclear fraction of primary tumors from two malignant mesothelioma patients
  • In HEK293 cells, CD26 forms lacking part of the extracellular region did not reach the nucleus, although they were expressed on the cell surface and still bound YS110
  • In JMN cells, nystatin, an inhibitor of the caveolin pathway, impaired uptake and nuclear localization of CD26 and YS110
  • In mice with JMN tumors, labeled YS110 injected directly into the center of the tumor accumulated in cell nuclei at 1 and 6 hours
  • In JMN cells, binding of CD26 to a DNA sequence (CAS162) located near the POLR2A gene increased with YS110 compared with control antibody
  • In JMN cells, POLR2A mRNA fell significantly after YS110 or 1F7 treatment compared with controls
  • In JMN cells, nystatin pretreatment significantly overrode the YS110-induced repression of POLR2A
  • A form of YS110 lacking its Fc region also lowered POLR2A, which the authors took to mean the effect does not depend on the Fc domain
  • In JMN cells, knocking down POLR2A with two RNA interference constructs inhibited proliferation
• The authors' conclusion: The authors concluded that YS110-induced nuclear localization of CD26 promotes repression of the POLR2A gene, resulting in growth suppression of cancer cells
• Limitations the authors state:
  • The authors did not identify the region of CD26 needed for binding to DNA
  • The authors state it is unknown whether the extent of nuclear CD26 depends on cancer type, tumor stage or environment

Topics

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Glycoprotein, STEM, Metastasis, Translocation.

Related studies

• A humanized anti-CD26 monoclonal antibody inhibits cell growth of malignant mesothelioma via retarded G2/M cell cycle transition — M. Hayashi, H. Madokoro, et al. (2016)
• Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect — K. Yamada, M. Hayashi, et al. (2009)
• Establishment of monoclonal anti-human CD26 antibodies suitable for immunostaining of formalin-fixed tissue — R. Hatano, T. Yamada, et al. (2014)
• First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers — E. Angevin, N. Isambert, et al. (2017)
• CD9 negatively regulates CD26 expression and inhibits CD26-mediated enhancement of invasive potential of malignant mesothelioma cells — T. Okamoto, S. Iwata, et al. (2014)
• Phase 1b Multicenter Study of SG001, a Humanized Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors — J. Fang, O. Jiang, et al. (2025)

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