2. Academic Validation
  3. Cooperation between SIX1 and DHX9 transcriptionally regulates integrin-focal adhesion signaling mediated metastasis and sunitinib resistance in KIRC

Cooperation between SIX1 and DHX9 transcriptionally regulates integrin-focal adhesion signaling mediated metastasis and sunitinib resistance in KIRC

  • Oncogene. 2024 Sep;43(39):2951-2969. doi: 10.1038/s41388-024-03126-w.
Shiyu Huang # 1 2 3,  Juncheng Hu # 1 2,  Min Hu # 4,  Yanguang Hou 1 2,  Banghua Zhang 1 2 5,  Jiachen Liu 1 2,  Xiuheng Liu 6 7,  Zhiyuan Chen 8 9,  Lei Wang 10 11
Affiliations

Affiliations

  • 1 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 2 Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 3 Central Laboratory, Renmin Hospital of Wuhan University, 430060, Wuhan, Hubei, China.
  • 4 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
  • 5 Hubei Key Laboratory of Digestive System Disease, Wuhan, 430060, China.
  • 6 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. drliuxh@hotmail.com.
  • 7 Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. drliuxh@hotmail.com.
  • 8 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. chenzhiyuan163@163.com.
  • 9 Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. chenzhiyuan163@163.com.
  • 10 Department of Urology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. drwanglei@whu.edu.cn.
  • 11 Institute of Urologic Disease, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China. drwanglei@whu.edu.cn.
  • # Contributed equally.
PMID: 39174859 DOI: 10.1038/s41388-024-03126-w
Abstract

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.

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