title: Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia.
abstract: One of the hallmarks of cancer, global gene expression alteration, is closely associated with the development and malignant characteristics associated with adult T-cell leukemia (ATL) as well as other cancers. Here, we show that aberrant overexpression of the Ellis Van Creveld (EVC) family is responsible for cellular Hedgehog (HH) activation, which provides the pro-survival ability of ATL cells. Using microarray, quantitative RT-PCR and immunohistochemistry we have demonstrated that EVC is significantly upregulated in ATL and human T-cell leukemia virus type I (HTLV-1)-infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. The HTLV-1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of shRNA targeting EVC, as well as the transcription factors for HH signaling, diminishes the HH activation and leads to apoptotic death in ATL cell lines. We also showed that a HH signaling inhibitor, GANT61, induces strong apoptosis in the established ATL cell lines and patient-derived primary ATL cells. Therefore, our data indicate that HH activation is involved in the regulation of leukemic cell survival. The epigenetically deregulated EVC appears to play an important role for HH activation. The possible use of EVC as a specific cell marker and a novel drug target for HTLV-1-infected T-cells is implicated by these findings. The HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamagishi
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamochi
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.forename: Dai
authors.initials: D
authors.lastname: Fujikawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakashima
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D016022:Case-Control Studies; D002470:Cell Survival; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D016356:Gene Products, tax / Q000502:physiology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; C406058:EVC protein, human; C551027:GANT 61; D016356:Gene Products, tax; D053823:Hedgehog Proteins; D008565:Membrane Proteins; D011506:Proteins; D011725:Pyridines; D011743:Pyrimidines; C514970:tax protein, Human T-lymphotrophic virus 1
keywords: ATL; EVC; HTLV-1; Hedgehog; epigenetics