Expression of ISL1 and its partners in prostate cancer progression and neuroendocrine differentiation

J Cancer Res Clin Oncol. 2021 Aug;147(8):2223-2231. doi: 10.1007/s00432-021-03634-2. Epub 2021 Apr 16.


Introduction and objectives: ISL1 serves as a biomarker of metastasis and neuroendocrine neoplasia in multiple tumors. However, the expression and relation of ISL1 to other biomarkers in prostate cancer have not been fully elucidated. Here, we characterize the expression of ISL1 and its partners in PCa and document its association to disease progression and post castration resistance neuroendocrine differentiation.

Methods: The expression of ISL1 was interrogated in > 6000 primary samples from the Decipher GRID registry and 250 mCRPC samples to assess its prognostic value and relation to neuroendocrine differentiation.

Results: ISL1 was highly correlated to MEIS genes and other genes related to cell motility. ISL1 down-regulation in PCa was associated with cancer progression, aggressive primary tumors, and metastatic outcome. We found that ISL1 is highly correlated to MEIS genes across multiple primary PCa and mCRPC cohorts. The expression of ISL1 and MEIS genes were significantly and inversely related to metastasis-free survival and lethal disease, and were downregulated in CRPC and hormone naïve metastatic tumors but showed upregulation in neuroendocrine tumors. Co-immunoprecipitation showed MEIS2 and ISL1 interacting with each supporting their role in modulating transcriptional regulation and nominating this complex for potential targeted therapy.

Conclusions: ISL1 complex with MEIS2 serves a critical role in prostate tumor progression and its upregulation in mCRPC/NE provides a rationale for assessing the role of ISL1 and its associated protein in treatment resistance.

Keywords: Biomarker; ISL1; MEIS; Neuroendocrine; Prostate cancer.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • LIM-Homeodomain Proteins / genetics*
  • LIM-Homeodomain Proteins / metabolism
  • Male
  • Myeloid Ecotropic Viral Integration Site 1 Protein / genetics
  • Myeloid Ecotropic Viral Integration Site 1 Protein / metabolism
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / pathology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Biomarkers, Tumor
  • Homeodomain Proteins
  • LIM-Homeodomain Proteins
  • MEIS1 protein, human
  • MEIS2 protein, human
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Transcription Factors
  • insulin gene enhancer binding protein Isl-1