Epigenetic deregulation of EVC confers robust Hedgehog signaling in adult T-cell leukemia.

Cancer science

PubMedID: 24996003

Takahashi R, Yamagishi M, Nakano K, Yamochi T, Yamochi T, Fujikawa D, Nakashima M, Tanaka Y, Uchimaru K, Utsunomiya A, Watanabe T. Epigenetic deregulation of EVC confers robust Hedgehog signaling in adult T-cell leukemia. Cancer Sci. 2014;.
One of 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 Ellis Van Creveld (EVC) family is responsible for cellular Hedgehog (HH) activation, which provides the pro-survival ability of ATL cells. We have demonstrated using microarray, quantitative RT-PCR, and immunohistochemistry that EVC is significantly upregulated in ATL and HTLV-1-infected cells. Epigenetic marks, including histone H3 acetylation and Lys4 trimethylation, are specifically accumulated at the EVC locus in ATL samples. HTLV-1 Tax participates in the coordination of EVC expression in an epigenetic fashion. The treatment of shRNAs targeting EVC, as well as the transcription factors for HH signaling diminishes the HH activation and leads to apoptotic death in ATL cell lines. Finally, we also show 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 EVC1 as a specific cell marker and a novel drug target for HTLV-1 infected T-cells is implicated by these findings. HH inhibitors are suggested as drug candidates for ATL therapy. Our findings also suggest chromatin rearrangement associated with active histone markers in ATL. This article is protected by copyright. All rights reserved.