1. Academic Validation
  2. AF9 targets acetyl-modified STAT6 to diminish purine metabolism and accelerate cell apoptosis during metastasis

AF9 targets acetyl-modified STAT6 to diminish purine metabolism and accelerate cell apoptosis during metastasis

  • Cell Death Differ. 2023 Jun 12. doi: 10.1038/s41418-023-01172-7.
Jialiang Shao # 1 Tiezhu Shi # 2 Lianheng Chen 2 Xiang Wang 1 Hua Yu 3 Ninghan Feng 4 Xiongjun Wang 5
Affiliations

Affiliations

  • 1 Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China.
  • 2 School of Life Sciences, Guangzhou University, Guangzhou, 510006, China.
  • 3 School of Life Sciences, Guangzhou University, Guangzhou, 510006, China. yuhua@sibcb.ac.cn.
  • 4 Department of Urology, The Affiliated Wuxi No.2 Hospital of Nanjing Medical University, Jiangsu, 214002, China. ninghan.feng@njmu.edu.cn.
  • 5 School of Life Sciences, Guangzhou University, Guangzhou, 510006, China. xiongjunwang@sibs.ac.cn.
  • # Contributed equally.
Abstract

Cell migration and invasion are two important steps for tumour metastasis, and involved the behaviors including metabolism remodeling and anti-apoptosis. However, it's still elusive that Cancer cells how to antagonize Apoptosis during tumour metastasis. In this study, we observed that super elongation complex (SEC) subunit AF9 depletion exacerbated cell migration and invasion but reduced the Apoptosis during invasive migration. Mechanically, AF9 targeted acetyl (Ac)-STAT6 at lysine (K) 284 and blocked STAT6 transactivation on the promoter of such genes involved in regulating purine metabolism and metastasis, in turn induced Apoptosis of suspended cells. Of note, AcSTAT6-K284 was not induced by IL4 signaling but decreased by limited nutrition which triggered SIRT6 to remove acetyl group at STAT6-K284. The functional experiments proved that AcSTAT6-K284 attenuated cell migration and invasion depending on AF9 expression level. Animal metastatic study further confirmed the AF9/AcSTAT6-K284 axis existed and blocked kidney renal clear cell carcinoma (KIRC) metastasis. In clinical, both AF9 expression and AcSTAT6-K284 were decreased accompanied by the advanced tumour grade and positively correlated with KIRC patients' survival. Conclusively, we explored an inhibitory axis which not only suppressed tumour metastasis but also could be utilized for drug development to hamper KIRC metastasis.

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