Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Oncogene. 2019 Nov;38(45):7046-7059. doi: 10.1038/s41388-019-0944-x. Epub 2019 Aug 13.
Deleted in Liver Cancer 1 (DLC1) is a tumor suppressor gene deleted in many cancers, including angiosarcoma, an aggressive malignancy of endothelial cell derivation. DLC1-deficiency in primary endothelial cells causes the loss of cell contact inhibition of growth through incompletely defined mechanisms. We report that DLC1 is a regulator of YAP, a transcriptional coactivator of proliferation-promoting and tumor-promoting genes; when confluent, active/nuclear YAP was significantly more abundant in DLC1-deficient endothelial cells compared with control cells. We also found that YAP is a required effector of the loss of cell contact inhibition of growth manifested by DLC1-deficient endothelial cells, as the silencing of YAP prevents this loss. Consistently, human angiosarcomas specimens contained a significantly greater proportion of DLC1 tumor cells with nuclear YAP compared with the DLC1 normal cells in the adjacent tissue. Verteporfin, an inhibitor of YAP, significantly reduced angiosarcoma growth in mice. These results identify YAP as a previously unrecognized effector of DLC1 deficiency-associated loss of cell contact growth inhibition in endothelial cells and a potential therapeutic target in angiosarcoma.
肝癌缺失基因 1（DLC1）是许多癌症中缺失的肿瘤抑制基因，包括血管肉瘤，这是一种源自内皮细胞的侵袭性恶性肿瘤。DLC1 在原代内皮细胞中的缺失通过不完全明确的机制导致细胞接触抑制生长的丧失。我们报告说，DLC1 是 YAP 的调节剂，YAP 是促进增殖和肿瘤的基因的转录共激活因子；在细胞汇合时，与对照细胞相比，DLC1 缺陷型内皮细胞中活跃/核内 YAP 的丰度明显更高。我们还发现，YAP 是 DLC1 缺陷型内皮细胞表现出的细胞接触抑制生长丧失所必需的效应因子，因为沉默 YAP 可防止这种丧失。一致地，与相邻组织中的 DLC1 正常细胞相比，人血管肉瘤标本中含有核 YAP 的 DLC1 肿瘤细胞的比例明显更高。YAP 的抑制剂维替泊芬（verteporfin）显著减少了小鼠血管肉瘤的生长。这些结果表明 YAP 是以前未被识别的 DLC1 缺陷相关内皮细胞中细胞接触生长抑制丧失的效应因子，也是血管肉瘤的潜在治疗靶点。
