肾透明细胞癌（KIRC）细胞的高侵袭能力和获得性酪氨酸激酶抑制剂（TKI）耐药性仍然是延长晚期 KIRC 患者生存时间的障碍。在本研究中，我们报道了正弦眼同源盒 1 (SIX1) 在舒尼替尼耐药的 KIRC 细胞和转移性 KIRC 组织中表达上调。随后，我们发现 SIX1 通过粘着斑 (FA) 信号介导转移和舒尼替尼耐药，并且 SIX1 的敲除增强了 KIRC 中舒尼替尼的抗肿瘤效率。从机制上讲，整合素亚基β1 (ITGB1)是FA信号传导的上游基因，是SIX1的直接转录靶标。此外，我们发现DExH-box解旋酶9（DHX9）是SIX1诱导的ITGB1转录的重要介质，沉默SIX1/DHX9复合物的亚基可显着降低ITGB1的转录。 SIX1 的下调减弱了 DHX9 的核转位，并消除了 DHX9 与 ITGB1 启动子的结合。总的来说，我们的结果揭示了 KIRC 中的新信号轴 SIX1/ITGB1/FAK，并为转移性 KIRC 患者确定了一种新的治疗策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

High invasive capacity and acquired tyrosine kinase inhibitors (TKI) resistance of kidney renal clear cell carcinoma (KIRC) cells remain obstacles to prolonging the survival time of patients with advanced KIRC. In the present study, we reported that sine oculis homeobox 1 (SIX1) was upregulated in sunitinib-resistant KIRC cells and metastatic KIRC tissues. Subsequently, we found that SIX1 mediated metastasis and sunitinib resistance via Focal adhesion (FA) signaling, and knockdown of SIX1 enhanced the antitumor efficiency of sunitinib in KIRC. Mechanistically, Integrin subunit beta 1 (ITGB1), an upstream gene of FA signaling, was a direct transcriptional target of SIX1. In addition, we showed that DExH-box helicase 9 (DHX9) was an important mediator for SIX1-induced ITGB1 transcription, and silencing the subunits of SIX1/DHX9 complex significantly reduced transcription of ITGB1. Downregulation of SIX1 attenuated nuclear translocation of DHX9 and abrogated the binding of DHX9 to ITGB1 promoter. Collectively, our results unveiled a new signal axis SIX1/ITGB1/FAK in KIRC and identified a novel therapeutic strategy for metastatic KIRC patients.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.