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Poly(ADP‑ribose) polymerase 1/2 inhibitors decrease the ubiquitination of ALC1 mediated by CHFR in breast cancer

Yiran Wang1, Ying Wang1, Ning Wang1

  • 1Department of Oncology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China.

Oncology Reports
|July 20, 2019
PubMed

Insights

Poly(ADP‑ribose) polymerase (PARP) inhibitors can cause resistance by decreasing CHFR-mediated ubiquitination of ALC1. This leads to ALC1 accumulation, impacting DNA damage response drug efficacy in breast cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Poly(ADP‑ribose) polymerase (PARP) inhibitors are increasingly used in cancer therapy, necessitating research into resistance mechanisms.
  • CHFR, an E3 ubiquitin ligase, and ALC1, an oncogene involved in breast cancer metastasis, play roles in DNA damage response.
  • The mechanism by which PARylated PARP1 activates ALC1 at DNA damage sites is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism of ALC1 regulation by CHFR and its dependence on PARylation.
  • To investigate the impact of PARP1/2 inhibitors on ALC1 ubiquitination, degradation, and expression.
  • To understand how these interactions affect the efficacy of DNA damage response drugs in breast cancer.

Main Methods:

  • Mass spectrometry, western blot analysis, and immunoprecipitation to confirm CHFR-ALC1 interaction.
  • Generation of deletion mutants to map interaction domains.
  • Assessment of ALC1 ubiquitination, half-life, and transcriptional levels in the presence and absence of PARP1/2 inhibitors.

Main Results:

  • CHFR interacts with ALC1, requiring specific domains (CHFR PBZ, ALC1 PMD and MACRO) and PARylation.
  • CHFR-mediated ubiquitination of ALC1 leads to its degradation.
  • PARP1/2 inhibitors reduce ALC1 ubiquitination, causing ALC1 accumulation and increased expression.

Conclusions:

  • PARP1/2 inhibitors decrease ALC1 ubiquitination by CHFR, leading to ALC1 accumulation.
  • This accumulation of ALC1 may compromise the therapeutic effects of DNA damage response drugs in breast cancer.
  • Understanding this mechanism is crucial for optimizing PARP inhibitor-based cancer therapies.

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