Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
J Cell Sci. 2023 Aug 1;136(15). doi: 10.1242/jcs.261001. Epub 2023 Aug 9.
The non-receptor tyrosine kinase SRC is overexpressed and/or hyperactivated in various human cancers, and facilitates cancer progression by promoting invasion and metastasis. However, the mechanisms underlying SRC upregulation are poorly understood. In this study, we demonstrate that transforming growth factor-β (TGF-β) induces SRC expression at the transcriptional level by activating an intragenic the SRC enhancer. In the human breast epithelial cell line MCF10A, TGF-β1 stimulation upregulated one of the SRC promotors, the 1A promoter, resulting in increased SRC mRNA and protein levels. Chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the SMAD complex is recruited to three enhancer regions ∼15 kb upstream and downstream of the SRC promoter, and one of them is capable of activating the SRC promoter in response to TGF-β. JUN, a member of the activator protein (AP)-1 family, localises to the enhancer and regulates TGF-β-induced SRC expression. Furthermore, TGF-β-induced SRC upregulation plays a crucial role in epithelial-mesenchymal transition (EMT)-associated cell migration by activating the SRC-focal adhesion kinase (FAK) circuit. Overall, these results suggest that TGF-β-induced SRC upregulation promotes cancer cell invasion and metastasis in a subset of human malignancies.
非受体酪氨酸激酶 SRC 在各种人类癌症中过度表达和/或过度激活，并通过促进侵袭和转移促进癌症进展。然而，SRC 上调的机制尚不清楚。在这项研究中，我们证明转化生长因子-β（TGF-β）通过激活 SRC 增强子中的内含子来在转录水平上诱导 SRC 表达。在人乳腺上皮细胞系 MCF10A 中，TGF-β1 刺激上调了 SRC 启动子之一，即 1A 启动子，导致 SRC mRNA 和蛋白水平增加。染色质免疫沉淀（ChIP）-测序分析表明，SMAD 复合物被募集到 SRC 启动子上游和下游约 15kb 的三个增强子区域，其中一个能够响应 TGF-β 激活 SRC 启动子。激活蛋白（AP）-1 家族的成员 JUN 定位于增强子并调节 TGF-β 诱导的 SRC 表达。此外，TGF-β 诱导的 SRC 上调通过激活 SRC-黏着斑激酶（FAK）通路在 EMT 相关细胞迁移中起着至关重要的作用。总的来说，这些结果表明 TGF-β 诱导的 SRC 上调促进了人类恶性肿瘤中某些癌症细胞的侵袭和转移。
