Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
School of Medicine, Oregon Health & Science University, Portland, OR, 97239, USA.
Oncogene. 2019 Aug;38(34):6196-6210. doi: 10.1038/s41388-019-0865-8. Epub 2019 Jul 22.
Apoptosis of cancer cells occurs by a complex gene regulatory network. Here we showed that SOX7 was significantly downregulated in different cancer types, especially in lung and breast cancers. Low expression of SOX7 was associated with advantage stage of cancer with shorter overall survival. Cancer cells with loss of SOX7 promoted cell survival and colony formation, suppressed cellular apoptosis and produced a drug resistant phenotype against a variety of chemo/targeting therapeutic agents. Mechanistically, SOX7 induced cellular apoptosis through upregulation of genes associated with both P38 and apoptotic signaling pathway, as well as preventing the proteasome mediated degradation of pro-apoptotic protein BIM. Treatment of either a proteasome inhibitor MG132 or bortezomib, or with a p-ERK/MEK inhibitor U0126 attenuate the SOX7 promoted BIM degradation. We identified Panobinostat, an FDA approved pan-HDAC inhibitor, could elevate and restore SOX7 expression in SOX7 silenced lung cancer cells. Taken together, these data revealed an unappreciated role of SOX7 in regulation of cellular apoptosis through control of MAPK/ERK-BIM signaling.
癌细胞的凋亡是通过一个复杂的基因调控网络发生的。在这里，我们表明 SOX7 在不同的癌症类型中显著下调，尤其是在肺癌和乳腺癌中。SOX7 的低表达与癌症的优势阶段相关，具有较短的总生存期。缺失 SOX7 的癌细胞促进了细胞存活和集落形成，抑制了细胞凋亡，并对多种化疗/靶向治疗药物产生了耐药表型。从机制上讲，SOX7 通过上调与 P38 和凋亡信号通路相关的基因诱导细胞凋亡，并防止蛋白酶体介导的促凋亡蛋白 BIM 的降解。用蛋白酶体抑制剂 MG132 或硼替佐米处理，或用 p-ERK/MEK 抑制剂 U0126 处理，均可减弱 SOX7 促进的 BIM 降解。我们鉴定出 Panobinostat，一种 FDA 批准的 pan-HDAC 抑制剂，能够在 SOX7 沉默的肺癌细胞中上调和恢复 SOX7 的表达。总之，这些数据揭示了 SOX7 通过控制 MAPK/ERK-BIM 信号通路在调节细胞凋亡中的作用。
