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Antioxidant functions of DHHC3 suppress anti-cancer drug activities

Chandan Sharma1,2, Wei Yang3, Hanno Steen4

  • 1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. chandan_sharma@dfci.harvard.edu.

Cellular and Molecular Life Sciences : CMLS
|September 28, 2020
PubMed

Insights

Targeting protein acyltransferase DHHC3 enhances chemotherapy effectiveness by reducing cancer cell antioxidant defenses. This strategy boosts the potency of oxidative stress-inducing anti-cancer drugs.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Protein acylation, specifically palmitoylation, plays a role in cellular regulation.
  • The protein acyltransferase DHHC3's function in cancer drug resistance is not fully understood.
  • DHHC3 may influence cellular responses to oxidative stress and chemotherapy.

Purpose of the Study:

  • To identify protein substrates of DHHC3 using proteomic analysis.
  • To investigate the role of DHHC3 in modulating cancer cell sensitivity to chemotherapeutic agents.
  • To explore DHHC3's involvement in oxidative stress pathways relevant to cancer.

Main Methods:

  • Comparative mass spectrometry-based palmitoyl-proteomic analysis in breast and prostate cancer cell lines with and without DHHC3 ablation.
  • Assessment of oxidative stress levels following DHHC3 ablation and/or chemotherapeutic drug treatment.
  • Evaluation of anti-cancer cell activities and proliferation in response to DHHC3 targeting and drug combinations.

Main Results:

  • The first comprehensive lists of candidate DHHC3 protein substrates were generated, including numerous antioxidant/redox-regulatory proteins.
  • DHHC3 ablation was found to elevate oxidative stress and enhance the anti-growth effects of certain chemotherapeutic agents.
  • DHHC3 ablation synergized with the PARP inhibitor PJ-34, decreasing cell proliferation and increasing oxidative stress.

Conclusions:

  • DHHC3 ablation enhances the potency of oxidative stress-inducing anti-cancer drugs by impairing antioxidant mechanisms that confer drug resistance.
  • Targeting DHHC3 presents a potential strategy for improving the efficacy of specific chemotherapies.
  • The identified DHHC3 substrates offer insights into its broader functions in tumor growth modulation.
Keywords:
Chemotherapeutic agentsDHHC3Oxidative stressPARP inhibitorProtein acyl transferasesProtein palmitoylation

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