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 palmitoyl-proteomic 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.

蛋白酰基转移酶 DHHC3 的消融选择性地增强了几种化学治疗剂的抗癌细胞活性，但不增强激酶抑制剂的抗癌细胞活性。为了理解为什么会发生这种情况，我们使用基于比较质谱的棕榈酰蛋白质组学分析乳腺癌和前列腺癌细胞系，±DHHC3 消融，以获得由 DHHC3 棕榈酰化的候选蛋白质底物的第一个综合列表。推定的底物包括 22-28 种抗氧化/氧化还原调节蛋白，因此预测 DHHC3 应该具有抗氧化功能。与此一致，DHHC3 消融提高了氧化应激。此外，DHHC3 消融与化疗药物治疗一起，(a) 提高了氧化应激，具有大于累加效应，和 (b) 增强了化疗药物的抗生长作用。这些结果表明，DHHC3 消融通过禁用导致耐药性的抗氧化保护来增强化疗药物的效力。证实了这一概念，DHHC3 消融与另一种抗癌药物 PARP 抑制剂 PJ-34 协同作用，可减少细胞增殖并增加氧化应激。因此，靶向 DHHC3 可以成为选择性增强氧化应激诱导抗癌药物效力的有用策略。此外，全面鉴定 DHHC3 底物可以深入了解与体内肿瘤生长调节相关的其他 DHHC3 功能。以减少细胞增殖并增加氧化应激。因此，靶向 DHHC3 可以成为选择性增强氧化应激诱导抗癌药物效力的有用策略。此外，全面鉴定 DHHC3 底物可以深入了解与体内肿瘤生长调节相关的其他 DHHC3 功能。以减少细胞增殖并增加氧化应激。因此，靶向 DHHC3 可以成为选择性增强氧化应激诱导抗癌药物效力的有用策略。此外，全面鉴定 DHHC3 底物可以深入了解与体内肿瘤生长调节相关的其他 DHHC3 功能。