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KBTBD11 loss promotes AKT hyperactivation and therapeutic vulnerability in prostate cancer

Haoyue Sheng1,2,3, Guohai Shi1,2, Yawen Lu4

  • 1Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.

Oncogene
|September 22, 2025
PubMed

Insights

Loss of the KBTBD11 gene in prostate cancer increases AKT phosphorylation, driving tumor growth. This deficiency creates a vulnerability exploitable by AKT inhibitors, suggesting KBTBD11 as a predictive biomarker for targeted therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The PI3K-AKT pathway is frequently dysregulated in cancers, including prostate cancer.
  • Mechanisms driving this aberrant activation and effective targeting strategies remain unclear.

Purpose of the Study:

  • To investigate the role of KBTBD11 E3 ubiquitin ligase in regulating AKT signaling in prostate cancer.
  • To identify KBTBD11 as a potential therapeutic target or biomarker for prostate cancer treatment.

Main Methods:

  • Analysis of KBTBD11 gene deletion frequency in prostate cancer patient samples.
  • Assessment of AKT phosphorylation levels in relation to KBTBD11 status.
  • Investigation of KBTBD11's role in AKT ubiquitination (K27-linked vs. K63-linked chains).
  • Evaluation of KBTBD11 deficiency effects on prostate cancer cell growth in vitro and in vivo.
  • Testing the efficacy of AKT inhibitors in KBTBD11-deficient prostate cancer models.

Main Results:

  • KBTBD11 gene is frequently deleted in human prostate cancers.
  • KBTBD11 loss leads to increased AKT phosphorylation in prostate cancer cells and patient tissues.
  • KBTBD11 promotes K27-linked polyubiquitination of AKT, inhibiting its activation, while antagonizing K63-linked ubiquitination and phosphorylation.
  • KBTBD11 deficiency enhances prostate cancer cell proliferation but sensitizes tumors to AKT inhibitors.

Conclusions:

  • KBTBD11 acts as an upstream inhibitor of AKT signaling through K27-linked polyubiquitination.
  • KBTBD11 deletion is a potential biomarker for guiding AKT inhibitor therapy in prostate cancer.
  • Targeting the AKT pathway with inhibitors is a viable strategy for KBTBD11-deficient prostate cancers.

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