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M1C mediates LINE-1 transcription in PARP inhibitor-treated prostate cancer cells

Keisuke Shigeta1, Shinkichi Takamori2, Hiroki Ozawa2

  • 1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Department of Urology, Keio University School of Medicine, Tokyo, Japan.

Cancer Letters
|February 14, 2026
PubMed

Insights

The oncogenic M1C protein drives castration-resistant prostate cancer (CRPC) progression and resistance to PARP inhibitors by activating retrotransposons. Targeting M1C may improve CRPC treatment with PARP inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Advanced castration-resistant prostate cancer (CRPC) shows response to PARP inhibitors, but only when homologous recombination (HR) is defective.
  • The oncogenic M1C protein is known to drive CRPC progression.
  • The role of M1C in response to PARP inhibition remains unclear.

Purpose of the Study:

  • To investigate the role of the M1C protein in the response of HR-competent CRPC cells to PARP inhibition.
  • To elucidate the molecular mechanisms by which M1C influences drug resistance and genomic instability.

Main Methods:

  • Treatment of HR-competent CRPC cells with olaparib.
  • Analysis of M1C expression, ATM expression, KAP1 phosphorylation, and STING activation.
  • Quantification of LINE-1 (L1) and HERV-K retrotransposon transcripts and proteins.
  • Assessment of APOBEC3 (A3) gene expression.

Main Results:

  • Olaparib treatment induces M1C in HR-competent CRPC cells.
  • M1C drives ATM expression, KAP1 phosphorylation, STING activation, and subsequent derepression of L1 retrotransposons.
  • M1C is essential for activating L1 and HERV-K retrotransposons and APOBEC3 genes, leading to genomic instability and olaparib resistance.
  • M1C activates HERV-K genes and expression of the HERV-K ENV protein.

Conclusions:

  • M1C plays a critical role in mediating resistance to PARP inhibitors in HR-competent CRPC by activating L1 and HERV-K retrotransposons and APOBEC3 genes.
  • M1C is a potential therapeutic target for overcoming PARP inhibitor resistance in CRPC.
Keywords:
APOBEC3Castration-resistant prostate cancerHERV-KHomologous recombinationLINE-1M1COlaparibRetrotransposons

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