Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, 050018, Shijiazhuang, China.
Department of Molecular and Cellular Pathology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
Oncogene. 2019 May;38(21):4028-4046. doi: 10.1038/s41388-019-0698-5. Epub 2019 Jan 28.
The nuclear factor E2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) signaling cascades is a key transcriptional pathway governing cellular oxidative stress and tumor development. Mammalian hepatitis B X-interacting protein (HBXIP) has critical roles in modulating cancer malignance and tumor progression. However, whether HBXIP interacts with KEAP1 and NRF2 is unclear. Here, we found that HBXIP can effectually compete with NRF2 for binding with KEAP1 protein via its highly conserved GLNLG motif. The HBXIP-mediated reduction in NRF2-KEAP1 complexes promotes NRF2 accumulation and nuclear entry, which facilities the activation of antioxidant response element (ARE)-dependent signaling cascades, thereby reducing the accumulation of endogenous cellular reactive oxygen species (ROS). We also found a strong positive correlation between HBXIP expression and NRF2 expression in breast cancer cells, tissue microarrays and clinical breast cancer tissues. Furthermore, this positive correlation was further confirmed via analysis of 1905 clinical cases of breast carcinoma provided by the cancer genomics database cBioPortal. Strikingly, disrupting the HBXIP-KEAP1 axis via mutating the GLNLG motif of HBXIP leads to potent inhibition of the malignancy of breast carcinoma both in vivo and in vitro. Our findings broaden our understanding of HBXIP as a modulation factor of cellular oxidative stress and address a novel regulatory mechanism governing redox homeostasis and the progression of breast carcinoma.
核因子 E2 相关因子 2（NRF2）-Kelch 样 ECH 相关蛋白 1（KEAP1）信号级联是调节细胞氧化应激和肿瘤发展的关键转录途径。乙型肝炎 X 交互蛋白（HBXIP）在调节癌症恶性和肿瘤进展方面具有重要作用。然而，HBXIP 是否与 KEAP1 和 NRF2 相互作用尚不清楚。在这里，我们发现 HBXIP 可以通过其高度保守的 GLNLG 基序有效地与 KEAP1 蛋白竞争与 NRF2 的结合。HBXIP 介导的 NRF2-KEAP1 复合物减少促进 NRF2 积累和核内进入，这有利于抗氧化反应元件（ARE）依赖性信号级联的激活，从而减少内源性细胞活性氧（ROS）的积累。我们还发现乳腺癌细胞、组织微阵列和临床乳腺癌组织中 HBXIP 表达与 NRF2 表达之间存在很强的正相关性。此外，通过对癌症基因组数据库 cBioPortal 提供的 1905 例乳腺癌临床病例进行分析进一步证实了这种正相关性。引人注目的是，通过突变 HBXIP 的 GLNLG 基序破坏 HBXIP-KEAP1 轴导致体内和体外乳腺癌恶性的有效抑制。我们的研究结果拓宽了我们对 HBXIP 作为细胞氧化应激调节因子的认识，并提出了一种新的调节机制，可控制氧化还原平衡和乳腺癌的进展。
