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.

Targeting Transcription Factors for Cancer Treatment

“…GANT61 inhibits GLI1/2-controlled luciferase expression at high doses (IC 50 ≈ 10 µM), abolishes GLI1-regulated genes [ 206 ] and subsequent megakaryocytic differentiation [ 207 ]. GANT61 also induces apoptosis in many cancer and leukemia models such as gastric cancer [ 208 ], Ewing sarcoma [ 209 ], biliary tract cancer [ 210 ], lung cancer [ 211 ], breast cancer [ 212 , 213 ], prostate carcinoma [ 214 , 215 ] and adult T-cell leukemia or acute myeloid leukemia [ 216 , 217 ]. GANT61 induces autophagy in pancreatic ductal adenocarcinoma cells and prevents cellular migration in osteosarcoma metastasis [ 218 ] and ovarian and breast cancer invasion [ 212 , 219 ].…”

Elevated Hedgehog activity contributes to attenuated DNA damage responses in aged hematopoietic cells

“…6a). Histone modifications in this circumscribed region enhance expression of both genes in various types of human leukemia [32]. Chromatinimmunoprecipitation (ChIP) on Lin-cells revealed an agingassociated reduction in repressive marks (H3K27-trimethylation), while activating H3K4-trimethylation marks were unchanged (Supplemental Fig.…”

Ellis‐van Creveld syndrome in a patient from Tanzania

“…It is suggestive that rarely in EVC syndrome with mutations in either EVC gene a myelodysplastic change exists. A study on adult T‐cell leukemia showed aberrant upregulation of EVC and EVC2 gene products which are implicated in hedgehog signaling, a specific control pathway implicated in bone marrow function (Takahashi et al, ). The causal relation with our patient's abnormal hematology remained unclear, but warrants follow‐up.…”