Int J Biol Sci 2022; 18(7):2833-2850. doi:10.7150/ijbs.70544 This issue

Research Paper

ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance

Jiefeng Huang1,2,4*, Jie Li3,4*, Jun Tang4, Yushen Wu4,5, Fengsheng Dai4, Ziying Yi4,5, Yan Wang4, Yunhai Li4,5, Yue Wu4, Guosheng Ren4,5✉, Tingxiu Xiang6✉

1. Department of Breast and Thyroid Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
2. Department of General Surgery, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China
3. Department of Dermatology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
4. Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
5. Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
6. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, China
* These authors contributed equally to this work.

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Citation:
Huang J, Li J, Tang J, Wu Y, Dai F, Yi Z, Wang Y, Li Y, Wu Y, Ren G, Xiang T. ZDHHC22-mediated mTOR palmitoylation restrains breast cancer growth and endocrine therapy resistance. Int J Biol Sci 2022; 18(7):2833-2850. doi:10.7150/ijbs.70544. Available from https://www.ijbs.com/v18p2833.htm

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Abstract

Graphic abstract

Palmitoylation is essential for the classic hallmarks of cancers through regulating protein stability and protein-protein interactions. ZDHHC22, as a well-known member of palmitoyltrans-ferase family, its role has not been revealed in cancer. We found ZDHHC22 expression was significantly lower in estrogen receptor (ER) negative breast cancer (BrCa) tissues and cell lines, and its expression was positively corelated with the clinical prognosis of BrCa patients. The lower expression of ZDHHC22 might be caused by its promoter methylation. ZDHHC22 inhibited the proliferation capability of BrCa cells both in vitro and in vivo, depending on its encoding palmitoyltransferase activity. In terms of the mechanisms, ZDHHC22 reduced mTOR stability via palmitoylation and decreased the activation of the AKT signaling pathway. Furthermore, ectopic expression of ZDHHC22 could restore the sensitivity to tamoxifen therapy in MCF-7R cells. Collectively, ZDHHC22 may serve as a prognostic biomarker and therapeutic target, providing the theoretical foundation for exploring specific palmitoylation drugs targeted, especially for endocrine therapy-resistant BrCa patients.

Keywords: Breast cancer, ZDHHC22, Palmitoylation, mTOR, Endocrine therapy resistance