2. Academic Validation
  3. LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

LZTFL1 inhibits kidney tumor cell growth by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway

  • Oncogene. 2023 Mar 25;1-15. doi: 10.1038/s41388-023-02666-x.
Jun Lu # 1 2,  Liang-Min Fu # 1,  Yun Cao # 3,  Yong Fang # 1,  Jia-Zheng Cao 4,  Yi-Hui Pan 5,  Jun-Jie Cen 1 2,  Yan-Ping Liang 1 2,  Zhen-Hua Chen 1 2,  Jin-Huan Wei 1,  Yong Huang 6,  Mukhtar Adan Mumin 1,  Quan-Hui Xu 1,  Ying-Han Wang 1,  Jiang-Quan Zhu 1,  Hui Liang 7,  Zhu Wang 7,  Qiong Deng 7,  Wei Chen 1,  Xiao-Han Jin 8,  Zhi-Ping Liu 9,  Jun-Hang Luo 10
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
  • 2 Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Pathology, Sun Yat-sen University Cancer Center of Sun Yat-sen University, Guangzhou, People's Republic of China.
  • 4 Department of Urology, Jiangmen Central Hospital, Jiangmen, Guangdong Province, People's Republic of China.
  • 5 Department of Urology, The First People's Hospital of Changzhou, Changzhou, Jiangsu, People's Republic of China.
  • 6 Department of Emergency, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China.
  • 7 Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong Province, People's Republic of China.
  • 8 Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. jinxh5@mail.sysu.edu.cn.
  • 9 Departments of Internal Medicine and Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA. Zhi-Ping.Liu@UTsouthwestern.edu.
  • 10 Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. luojunh@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 36966254 DOI: 10.1038/s41388-023-02666-x
Abstract

LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various Cancer types including the kidney Cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing Akt through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.

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