Laboratory of Genome and Biosignals, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
J Cell Mol Med. 2022 Nov;26(22):5680-5689. doi: 10.1111/jcmm.17598. Epub 2022 Oct 25.
Zic family member 5 (ZIC5) is a transcription factor that promotes the survival of several cancer cell types. As ZIC5 is expressed at minimal levels in normal human adult tissues, it is a potential therapeutic target. In this study, we screened a chemical library containing 3398 compounds that includes pre-existing drugs and compounds with known effects to identify ZIC5 inhibitors. In the first screening, 18 hit compounds decreased GFP intensity in melanoma A375 cells overexpressing GFP-tagged ZIC5. In the second screening, five compounds that attenuated ZIC5 protein levels in A375 cells were identified. Among them, LL-Z1640-2 and patulin selectively induced apoptosis in melanoma cells expressing ZIC5, while only inducing very low levels of apoptosis in normal human melanocytes, which have no detectable ZIC5 expression. LL-Z1640-2 and patulin also induced apoptosis in BRAF inhibitor-resistant melanoma, pancreatic cancer, cholangiocarcinoma and colorectal cancer cells. LL-Z1640-2- and patulin-mediated suppression of melanoma proliferation were rescued by ZIC5 overexpression. These results suggest that LL-Z1640-2 and patulin are promising compounds that decrease ZIC5 expression to induce apoptosis in cancer cells.
锌指蛋白 5（ZIC5）是一种转录因子，可促进多种癌细胞类型的存活。由于 ZIC5 在正常成人组织中的表达水平极低，因此它是一个潜在的治疗靶点。在这项研究中，我们筛选了一个包含 3398 种化合物的化学文库，其中包括现有药物和具有已知作用的化合物，以鉴定 ZIC5 抑制剂。在第一轮筛选中，有 18 种候选化合物使过表达 GFP 标记的 ZIC5 的黑色素瘤 A375 细胞中的 GFP 强度降低。在第二轮筛选中，鉴定出了五种可降低 A375 细胞中 ZIC5 蛋白水平的化合物。其中，LL-Z1640-2 和棒曲霉素选择性地诱导表达 ZIC5 的黑色素瘤细胞凋亡，而对正常人类黑素细胞（无明显 ZIC5 表达）仅诱导非常低水平的凋亡。LL-Z1640-2 和棒曲霉素还可诱导 BRAF 抑制剂耐药的黑色素瘤、胰腺癌、胆管癌和结直肠癌细胞凋亡。LL-Z1640-2 和棒曲霉素介导的黑色素瘤增殖抑制作用可通过 ZIC5 过表达得到挽救。这些结果表明，LL-Z1640-2 和棒曲霉素是有前途的化合物，可通过降低 ZIC5 表达来诱导癌细胞凋亡。
