Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Research Center of Digestive Diseases, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
J Cell Mol Med. 2024 Jun;28(11):e18484. doi: 10.1111/jcmm.18484.
As an important protein encoded by hepatitis B virus (HBV), HBV X protein (HBx) plays an important role in the development of hepatocellular carcinoma (HCC). It has been shown that seven in absentia homologue 1 (SIAH1) could regulates the degradation of HBx through the ubiquitin-proteasome pathway. However, as a member of SIAH family, the regulatory effects of SIAH2 on HBx remain unclear. In this study, we first confirmed that SIAH2 could reduce the protein levels of HBx depending on its E3 ligase activity. Moreover, SIAH2 interacted with HBx and induced its K48-linked polyubiquitination and proteasomal degradation. Furthermore, we provided evidence that SIAH2 inhibits HBx-associated HCC cells proliferation by regulating HBx. In conclusion, our study identified a novel role for SIAH2 in promoting HBx degradation and SIAH2 exerts an inhibitory effect in the proliferation of HBx-associated HCC through inducing the degradation of HBx. Our study provides a new idea for the targeted degradation of HBx and may have great huge significance into providing novel evidence for the targeted therapy of HBV-infected HCC.
作为乙型肝炎病毒（HBV）编码的一种重要蛋白，HBV X 蛋白（HBx）在肝细胞癌（HCC）的发展中起着重要作用。已经表明，七次跨膜结构域蛋白 1（SIAH1）可以通过泛素-蛋白酶体途径调节 HBx 的降解。然而，作为 SIAH 家族的一员，SIAH2 对 HBx 的调节作用尚不清楚。在这项研究中，我们首先证实 SIAH2 可以通过其 E3 连接酶活性降低 HBx 的蛋白水平。此外，SIAH2 与 HBx 相互作用，并诱导其 K48 连接的多聚泛素化和蛋白酶体降解。此外，我们提供了证据表明，SIAH2 通过调节 HBx 抑制 HBx 相关 HCC 细胞的增殖。总之，我们的研究确定了 SIAH2 在促进 HBx 降解中的新作用，并且通过诱导 HBx 的降解，SIAH2 在 HBx 相关 HCC 的增殖中发挥抑制作用。我们的研究为 HBx 的靶向降解提供了一个新的思路，并可能为 HBV 感染 HCC 的靶向治疗提供新的有价值的证据。
