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

Jialiang Shao1, Tiezhu Shi2, Lianheng Chen2

  • 1Department of Urology, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, China.

Cell Death and Differentiation
|June 12, 2023
PubMed

Insights

The super elongation complex (SEC) subunit AF9 antagonizes apoptosis during tumor metastasis. Its depletion enhances migration, while acetylation of STAT6 at lysine 284 (AcSTAT6-K284) inhibits metastasis and improves survival in kidney cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Cell migration and invasion are critical for tumor metastasis, involving metabolic remodeling and anti-apoptotic mechanisms.
  • The precise ways cancer cells evade apoptosis during metastasis remain unclear.
  • Understanding these mechanisms is crucial for developing targeted anti-cancer therapies.

Purpose of the Study:

  • To investigate the role of the super elongation complex (SEC) subunit AF9 in regulating apoptosis during tumor cell migration and invasion.
  • To elucidate the molecular mechanism by which AF9 influences cell death and metastasis.
  • To explore the potential of the AF9/AcSTAT6-K284 axis as a therapeutic target for kidney renal clear cell carcinoma (KIRC) metastasis.

Main Methods:

  • Depletion of AF9 in cancer cells to assess effects on migration, invasion, and apoptosis.
  • Identification of AF9's interaction with acetylated STAT6 (AcSTAT6) at lysine 284 (K284).
  • Analysis of STAT6 transactivation, purine metabolism, and gene regulation.
  • In vivo animal metastasis models and clinical data analysis of KIRC patients.

Main Results:

  • AF9 depletion increased cell migration and invasion while reducing apoptosis in invasive cells.
  • AF9 targets AcSTAT6-K284, inhibiting STAT6 transactivation of genes involved in purine metabolism and metastasis, thereby inducing apoptosis in suspended cells.
  • AcSTAT6-K284 levels were modulated by nutrient availability via SIRT6, independent of IL4 signaling.
  • The AF9/AcSTAT6-K284 axis was confirmed to inhibit KIRC metastasis in vivo and in clinical samples, with decreased AF9 and AcSTAT6-K284 correlating with advanced tumor grade and poorer survival.

Conclusions:

  • The study identifies a novel inhibitory axis, AF9/AcSTAT6-K284, that suppresses tumor metastasis by regulating apoptosis and purine metabolism.
  • AcSTAT6-K284 acts as a crucial regulator of cell survival during invasive migration, independent of IL4 signaling.
  • This axis represents a potential therapeutic target for inhibiting KIRC metastasis and improving patient outcomes.

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