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Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

The oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor alpha (PML/RARα) is critical for acute promyelocytic leukemia (APL). PML/RARα initiates APL by blocking the differentiation and increasing the self-renewal of leukemic cells. The standard clinical therapies all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which induce PML/RARα proteolysis, have dramatically improved the prognosis of APL patients. However, the emergence of mutations conferring resistance to ATRA and ATO has created challenges in the treatment of APL patients. Exploring pathways that modulate the oncogenic activity of PML/RARα could help develop novel therapeutic strategies for APL, particularly for drug-resistant APL. Herein, we demonstrated for the first time that palmitoylation of PML/RARα was a critical determinant of its oncogenic activity. PML/RARα palmitoylation was found to be catalyzed mainly by the palmitoyltransferase ZDHHC3. Mechanistically, ZDHHC3-mediated palmitoylation regulated the oncogenic transcriptional activity of PML/RARα and APL pathogenesis. The knockdown or overexpression of ZDHHC3 had respective effects on the expression of proliferation- and differentiation-related genes. Consistently, the depletion or inhibition of ZDHHC3 could significantly arrest the malignant progression of APL, particularly drug-resistant APL, whereas ZDHHC3 overexpression appeared to have a promoting effect on the malignant progression of APL. Thus, our study not only reveals palmitoylation as a novel regulatory mechanism that modulates PML/RARα oncogenic activity but also identifies ZDHHC3 as a potential therapeutic target for APL, including drug-resistant APL.

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Fig. 1: PML/RARα undergoes S-palmitoylation in the RARα region.
Fig. 2: PML/RARα is palmitoylated by ZDHHC3 in the RARα region.
Fig. 3: ZDHHC3 regulates the oncogenic activity of PML/RARα.
Fig. 4: ZDHHC3 knockdown reshaped the proliferation and differentiation landscape of APL.
Fig. 5: ZDHHC3-mediated palmitoylation is essential for transcriptional function of PML/RARα.
Fig. 6: Inhibition of palmitoylation showed therapeutic effect on APL and drug-resistant APL.

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Acknowledgements

This study was supported by grants from the National Key R&D Program of China (2021YFA1300604), the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR24H310001), and the Fundamental Research Funds for the Central Universities.

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Author notes

  1. These authors contributed equally: Xue-jing Shao, Wei Wang, Ai-xiao Xu

Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China

    Xue-jing Shao, Wei Wang, Ai-xiao Xu, Xiao-tian Qi, Min-yi Cai, Wen-xin Du, Ji Cao, Qiao-jun He, Mei-dan Ying & Bo Yang

  2. Cancer Center, Zhejiang University, Hangzhou, 310058, China

    Ji Cao, Qiao-jun He & Mei-dan Ying

  3. School of Medicine, Hangzhou City University, Hangzhou, 310015, China

    Mei-dan Ying & Bo Yang

  4. Division of Hematology-Oncology, the Children’s Hospital Zhejiang University School of Medicine, Hangzhou, 310015, China

    Mei-dan Ying

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Contributions

BY, MDY and XJS conceived the study and analyzed data; MDY, XJS and WW wrote the manuscript; XJS, WW, AXX, XTQ, and WXD performed the Western blotting and RNA sequencing assay; WW and MYC performed the cellular proliferation analysis and soft agar formation assay; JC and QJH conceived the experiments and helped organize the paper.

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Correspondence to Mei-dan Ying or Bo Yang.

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Shao, Xj., Wang, W., Xu, Ax. et al. Palmitoyltransferase ZDHHC3 is essential for the oncogenic activity of PML/RARα in acute promyelocytic leukemia. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01371-z

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