Knockdown of XAB2 enhances all-trans retinoic acid-induced cellular differentiation in all-trans retinoic acid-sensitive and -resistant cancer cells.
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 alpha (RARalpha) 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.
Ohnuma-Ishikawa
Kumiko
K
Department of Pediatrics, Graduate Medical School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 11308519, Japan.
Morio
Tomohiro
T
Yamada
Takayuki
T
Sugawara
Yuji
Y
Ono
Makoto
M
Nagasawa
Masayuki
M
Yasuda
Akio
A
Morimoto
Chikao
C
Ohnuma
Kei
K
Dang
Nam H
NH
Hosoi
Hajime
H
Verdin
Eric
E
Mizutani
Shuki
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000099186:Histone Deacetylase 3
D000970:Antineoplastic Agents; D006655:Histone Deacetylases; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D014212:Tretinoin; D000099186:Histone Deacetylase 3; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C417244:XAB2 protein, human