Palmer Colin J, Galan-Caridad Jose M, Weisberg Stuart P, Lei Liang, Esquilin Jose M, Croft Gist F, Wainwright Brandon, Canoll Peter, Owens David M, Reizis Boris
Department of Microbiology and Immunology, Columbia University Medical Center, New York, New York.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
Cancer Res. 2014 Oct 15;74(20):5914-24. doi: 10.1158/0008-5472.CAN-14-0834. Epub 2014 Aug 27.
The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis. Hh-induced tumors arise from various tissues and they may be indolent or aggressive, as is the case with skin basal cell carcinoma (BCC) or cerebellar medulloblastoma, respectively. Little is known about common cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of hematopoietic and embryonic stem cells, as well as for the propagation of acute myeloid and T-lymphoblastic leukemias. We report here that Zfx facilitates the development of experimental BCC and medulloblastoma in mice initiated by deletion of the Hh inhibitory receptor Ptch1. Simultaneous deletion of Zfx along with Ptch1 prevented BCC formation and delayed medulloblastoma development. In contrast, Zfx was dispensable for tumorigenesis in a mouse model of glioblastoma. We used genome-wide expression and chromatin-binding analysis in a human medulloblastoma cell line to characterize direct, evolutionarily conserved targets of Zfx, identifying Dis3L and Ube2j1 as two targets required for the growth of the human medulloblastoma cells. Our results establish Zfx as a common cell-intrinsic regulator of diverse Hh-induced tumors, with implications for the definition of new therapeutic targets in these malignancies.
刺猬信号通路(Hh)调节后生动物的正常发育和细胞增殖,但其异常激活可促进肿瘤发生。Hh诱导的肿瘤起源于各种组织,可能生长缓慢或具有侵袭性,分别如皮肤基底细胞癌(BCC)或小脑髓母细胞瘤。对于控制这类不同的Hh依赖性肿瘤发生发展的常见细胞内在因子,人们了解甚少。转录因子Zfx是造血干细胞和胚胎干细胞自我更新以及急性髓系白血病和T淋巴细胞白血病增殖所必需的。我们在此报告,在通过缺失Hh抑制受体Ptch1引发的小鼠实验性BCC和髓母细胞瘤发生过程中,Zfx起到促进作用。同时缺失Zfx和Ptch1可阻止BCC形成并延缓髓母细胞瘤发展。相比之下,在胶质母细胞瘤小鼠模型中,Zfx对肿瘤发生并不必要。我们在人髓母细胞瘤细胞系中进行全基因组表达和染色质结合分析,以鉴定Zfx直接的、进化保守的靶标,确定Dis3L和Ube2j1是人类髓母细胞瘤细胞生长所需的两个靶标。我们的结果确立了Zfx作为多种Hh诱导肿瘤的常见细胞内在调节因子的地位,这对于定义这些恶性肿瘤的新治疗靶点具有重要意义。