Antioxidant functions of DHHC3 suppress anti-cancer drug activities
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Antioxidant functions of DHHC3 suppress anti‑cancer drug activities Chandan Sharma1,4 · Wei Yang2 · Hanno Steen3 · Michael R. Freeman2 · Martin E. Hemler1 Received: 4 May 2020 / Revised: 11 August 2020 / Accepted: 3 September 2020 © Springer Nature Switzerland AG 2020
Abstract Ablation of protein acyltransferase DHHC3 selectively enhanced the anti-cancer cell activities of several chemotherapeutic agents, but not kinase inhibitors. To understand why this occurs, we used comparative mass spectrometry-based palmitoylproteomic analysis of breast and prostate cancer cell lines, ± DHHC3 ablation, to obtain the first comprehensive lists of candidate protein substrates palmitoylated by DHHC3. Putative substrates included 22–28 antioxidant/redox-regulatory proteins, thus predicting that DHHC3 should have antioxidant functions. Consistent with this, DHHC3 ablation elevated oxidative stress. Furthermore, DHHC3 ablation, together with chemotherapeutic drug treatment, (a) elevated oxidative stress, with a greater than additive effect, and (b) enhanced the anti-growth effects of the chemotherapeutic agents. These results suggest that DHHC3 ablation enhances chemotherapeutic drug potency by disabling the antioxidant protections that contribute to drug resistance. Affirming this concept, DHHC3 ablation synergized with another anti-cancer drug, PARP inhibitor PJ-34, to decrease cell proliferation and increase oxidative stress. Hence, DHHC3 targeting can be a useful strategy for selectively enhancing potency of oxidative stress-inducing anti-cancer drugs. Also, comprehensive identification of DHHC3 substrates provides insight into other DHHC3 functions, relevant to in vivo tumor growth modulation. Keywords Chemotherapeutic agents · DHHC3 · Oxidative stress · PARP inhibitor · Protein palmitoylation · Protein acyl transferases Abbreviations DHHC3 Enzyme #3 in a family containing Asp–His–His–Cys motif NPC1 NPC intracellular cholesterol transporter 1
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03635-3) contains supplementary material, which is available to authorized users.
PalmPISC Palmitoyl protein identification and site characterization PARP Poly (ADP-ribose) polymerase PRDX4 Peroxiredoxin 4 SILAC Stable isotope labeling by amino acids in cell culture TMEM192 Transmembrane protein 192 TMX1 and TMX3 Thioredoxin related transmembrane proteins 1 and 3
* Chandan Sharma [email protected]
Introduction
* Martin E. Hemler [email protected]
The DHHC (Asp-His-His-Cys) enzyme family, which includes at least 23 members in mammals, is responsible for most protein S-palmitoylation (hereafter termed palmitoylation) in the animal kingdom [1]. DHHC enzymes can have oncogenic, tumor suppressor and prognostic roles in cancer [2, 3]. The DHHC3 (GODZ) enzyme is elevated in human breast cancer and elevated gene expression correlates with reduced survival in patients with breast cancer and si
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