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DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer

Sung-Jen Wei1, In-Hyoung Yang1, Ismail S Mohiuddin2

  • 1Cancer Center, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.

Biochimica Et Biophysica Acta. Gene Regulatory Mechanisms
|April 28, 2023
PubMed

Insights

A novel DNA-PKcs/OCT4/c-MYC pathway drives high c-MYC expression in small cell lung cancer (SCLC). Targeting this pathway with inhibitors shows anticancer activity, offering a new therapeutic strategy for SCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Small cell lung cancer (SCLC) is a neuroendocrine tumor characterized by rapid metastasis and chemotherapy resistance.
  • Genomic instability, driven by high mutation burden and alterations in TP53, RB1, and MYC, presents challenges for targeted therapy development.
  • A previously identified OCT4-induced MYC pathway in neuroblastoma suggests a potential mechanism in other neuroendocrine tumors.

Purpose of the Study:

  • To investigate the role of the OCT4/MYC pathway in SCLC.
  • To identify potential therapeutic targets within this pathway.
  • To evaluate the efficacy of targeting this pathway in preclinical SCLC models.

Main Methods:

  • Tumor microarray analysis of clinical SCLC samples and preclinical models.
  • Correlation of c-MYC protein expression with genomic amplification.
  • Confirmation of OCT4 and DNA-PKcs interaction and binding sites.
  • Gene knockdown experiments for POU5F1 (OCT4) and PRKDC (DNA-PKcs).
  • Assessment of anticancer activity using DNA-PKcs inhibitors and a protein-protein interaction inhibitor.

Main Results:

  • A correlation between c-MYC and OCT4/MAPKAPK2 expression was observed in SCLC.
  • Amplification-independent activation of MYC was identified in some SCLC cell lines.
  • Direct interaction between OCT4 and DNA-PKcs was confirmed, with OCT4 binding to the MYC promoter/enhancer region.
  • Knockdown of OCT4 and DNA-PKcs reduced c-MYC expression.
  • Targeting the DNA-PKcs/OCT4/c-MYC pathway demonstrated significant anticancer activity in SCLC cell lines and xenografts.

Conclusions:

  • The DNA-PKcs/OCT4/c-MYC pathway is present and active in SCLC.
  • DNA-PKcs mediates high c-MYC expression in SCLC, independent of MYC amplification.
  • This pathway represents a promising new therapeutic target for SCLC, particularly in cases with high c-MYC expression.
Keywords:
DNA-PKcsNarciclasineSmall cell lung cancerTranscriptional activationc-MYC

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