Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Pfizer Inc. Integrative Biotechnology Group, Pearl River, New York.
Cancer Res. 2020 May 1;80(9):1819-1832. doi: 10.1158/0008-5472.CAN-19-3116. Epub 2020 Mar 3.
RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 ( ), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients. These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
RING 指 E3 连接酶在炎症级联反应、细胞凋亡和癌症的调控中起着重要作用。然而，它们在 TGFβ/SMAD 信号通路中的作用相对未知。SMAD3 及其衔接蛋白（如 β2SP）是 TGFβ 信号的重要介质，调节基因表达，抑制多种癌症中的干细胞样表型，包括肝细胞癌（HCC）。在这里，E3 连接酶 PJA1 促进了磷酸化 SMAD3 的泛素化和降解，破坏了多个 HCC 细胞系中 SMAD3/β2SP 依赖性肿瘤抑制途径。在 SMAD3 缺失的小鼠（ ）中，PJA1 的过表达促进了肝干细胞的转化。对 PJA1 敲低和 TGFβ1 信号转导调控基因的分析显示，有 1584 个共同上调基因和 1280 个共同下调基因，包括许多与癌症相关的基因。E3 连接酶抑制剂 RTA405 增强了 SMAD3 调节的基因表达，并减少了 HCC 细胞在培养物和 HCC 肿瘤异种移植物中的生长，表明抑制 PJA1 可能有益于治疗 HCC 或预防高危患者的 HCC 发展。这些发现为调控 TGFβ 在肝致癌中的肿瘤抑制功能提供了一种新的机制。
