This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ohnuma-Ishikawa, K. Articles by Mizutani, S. Search for Related Content PubMed PubMed Citation Articles by Ohnuma-Ishikawa, K. Articles by Mizutani, S.

Knockdown of XAB2 Enhances All-Trans Retinoic Acid–Induced Cellular Differentiation in All-Trans Retinoic Acid–Sensitive and –Resistant Cancer Cells

¹ Department of Pediatrics, Graduate Medical School, Tokyo Medical and Dental University; ² Life Science Laboratory, Materials Laboratories, Sony Corporation; ³ Department of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; ⁴ Department of Hematologic Malignancies, Nevada Cancer Institute, Las Vegas, Nevada; ⁵ Departments of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan; and ⁶ Gladstone Institute of Virology and Immunology, University of California, San Francisco, California

Requests for reprints: Shuki Mizutani, Department of Pediatrics and Developmental Biology, Graduate Medical School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5244; Fax: 81-3-3818-7181; E-mail: smizutani.ped{at}tmd.ac.jp.

Xeroderma pigmentosum group A (XPA)–binding protein 2 (XAB2) is composed of 855 amino acids, contains 15 tetratricopeptide repeat motifs, and associates with Cockayne syndrome group A and B proteins and RNA polymerase II, as well as XPA. In vitro and in vivo studies showed that XAB2 is involved in pre-mRNA splicing, transcription, and transcription-coupled DNA repair, leading to preimplantation lethality, and is essential for mouse embryogenesis. Retinoids are effective for the treatment of preneoplastic diseases including xeroderma pigmentosum and other dermatologic diseases such as photoaging. We therefore focused on defining the effect of XAB2 on cellular differentiation in the presence of ATRA treatment. In the present study, we showed that overexpression of XAB2 inhibited ATRA-induced cellular differentiation in human rhabdomyosarcoma cell line, and that knockdown of XAB2 by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation in the human promyelocytic leukemia cell line HL60 at both physiologic (10^–9–10^–8 mol/L) and therapeutic (10^–7 mol/L) concentrations of ATRA. Moreover, we found that XAB2 was associated with retinoic acid receptor (RAR) and histone deacetylase 3 in the nuclei. Finally, using siRNA against XAB2, we showed that the ATRA-resistant neuroblastoma cell line IMR-32 underwent cellular differentiation induced by ATRA at a therapeutic concentration (10^–6 mol/L). These results strongly suggest that XAB2 is a component of the RAR corepressor complex with an inhibitory effect on ATRA-induced cellular differentiation and that XAB2 plays a role in ATRA-mediated cellular differentiation as an important aspect of cancer therapy. [Cancer Res 2007;67(3):1019–29]

This article has been cited by other articles:

				I. Kuraoka, S. Ito, T. Wada, M. Hayashida, L. Lee, M. Saijo, Y. Nakatsu, M. Matsumoto, T. Matsunaga, H. Handa, et al. Isolation of XAB2 Complex Involved in Pre-mRNA Splicing, Transcription, and Transcription-coupled Repair J. Biol. Chem., January 11, 2008; 283(2): 940 - 950. [Abstract] [Full Text] [PDF]