a Massachusetts General Hospital , Cutaneous Biology Research Center , Charlestown , MA , USA.
b Department of Dermatology , Harvard Medical School , Boston , MA , USA.
Autophagy. 2019 Apr;15(4):738-739. doi: 10.1080/15548627.2019.1569936. Epub 2019 Jan 22.
In the tumor stroma, cancer-associated fibroblasts (CAFs) affect all aspects of tumor evolution. Whereas several programs leading to CAF activation have been elucidated, little is known about the impact of the microenvironment on the turnover of key CAF regulators. RBPJ/CSL is a transcriptional repressor that mediates NOTCH signaling and its down-modulation activates the gene expression program(s) leading to stromal senescence and CAF activation. We overview our evidence that conditions increasing macroautophagy/autophagy, as often found in the stroma of tumors, cause the down-modulation of the RBPJ protein. This event requires the autophagic machinery and is functionally relevant because it is associated with an increase of CAF effector gene expression. The mechanism involves the direct association with the autophagy receptor SQSTM1/p62, which is required for RBPJ down-modulation. As a reflection of increased autophagy in the stroma, both the RBPJ and SQSTM1 proteins are down-modulated in Squamous Cell Carcinoma (SCC) patient-derived CAFs. Increasing RBPJ cellular levels stabilizes SQSTM1 and down-modulates the autophagic process. Our findings identify an autophagy-initiated mechanism for RBPJ down-modulation leading to increased CAF gene expression.
在肿瘤基质中，癌症相关成纤维细胞（CAFs）影响肿瘤进化的各个方面。虽然已经阐明了几个导致 CAF 激活的程序，但对于微环境对关键 CAF 调节剂周转率的影响知之甚少。RBPJ/CSL 是一种转录抑制剂，可介导 NOTCH 信号，其下调激活导致基质衰老和 CAF 激活的基因表达程序。我们概述了我们的证据，即在肿瘤基质中经常发现的增加巨自噬/自噬的条件会导致 RBPJ 蛋白的下调。这一事件需要自噬机制，并且具有功能相关性，因为它与 CAF 效应基因表达的增加有关。该机制涉及与自噬受体 SQSTM1/p62 的直接关联，这对于 RBPJ 的下调是必需的。作为基质中自噬增加的反映，在鳞状细胞癌（SCC）患者来源的 CAFs 中，RBPJ 和 SQSTM1 蛋白均下调。增加 RBPJ 细胞水平稳定 SQSTM1 并下调自噬过程。我们的发现确定了一种自噬引发的 RBPJ 下调机制，导致 CAF 基因表达增加。
