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SETDB1-mediated repression of RhoB promotes EMT and metastatic progression in prostate cancer

Han Cong1, Fatemeh Seilani1, Ryan Goettl2

  • 1Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.

Oncogene
|July 8, 2026
PubMed

Insights

The study identifies SETDB1 as a key driver of prostate cancer metastasis by repressing RhoB. Targeting this SETDB1-RhoB pathway may offer new therapeutic strategies for advanced prostate cancer.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Metastatic castration-resistant prostate cancer (CRPC) presents significant clinical challenges.
  • Epithelial-mesenchymal transition (EMT) drives prostate cancer metastasis and therapy resistance.
  • Upstream epigenetic regulators of EMT in advanced prostate cancer are not fully understood.

Purpose of the Study:

  • To identify epigenetic mechanisms sustaining EMT in advanced prostate cancer.
  • To investigate the role of histone H3 lysine 9 (H3K9) methyltransferase SETDB1 in prostate cancer progression.
  • To elucidate the functional relationship between SETDB1 and RhoB in prostate cancer metastasis.

Main Methods:

  • Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing.
  • Functional assays including cell migration, invasion, and metastatic dissemination.
  • In vitro and in vivo prostate cancer models, including therapy-resistant models.
  • Antisense oligonucleotide (ASO)-mediated gene silencing.

Main Results:

  • SET domain bifurcated 1 (SETDB1) is upregulated and genomically amplified in metastatic CRPC.
  • SETDB1 directly represses RhoB expression via H3K9 methylation at the RhoB promoter.
  • SETDB1 depletion inhibits cell migration, invasion, and metastasis, which is reversed by RhoB restoration.
  • Loss of RhoB and EMT activation are observed in androgen signaling inhibitor-resistant prostate cancer models.

Conclusions:

  • A novel epigenetic pathway involving SETDB1-mediated repression of RhoB promotes EMT and metastasis in prostate cancer.
  • RhoB acts as a critical downstream effector of SETDB1 in driving prostate cancer progression.
  • Targeting the SETDB1-RhoB axis presents a potential therapeutic strategy for advanced and therapy-resistant prostate cancer.

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