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  3. Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism

Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism

  • Pharmacol Res. 2022 Nov 18;106558. doi: 10.1016/j.phrs.2022.106558.
Cheng Huang 1,  Liangping Su 1,  Yitian Chen 2,  Sangqing Wu 3,  Ruipu Sun 1,  Qiuping Xu 1,  Xiaoyi Qiu 1,  Ciqiu Yang 2,  Xiangzhan Kong 1,  Hongquan Qin 1,  Xinbao Zhao 4,  Xue Jiang 1,  Kun Wang 5,  Yinghua Zhu 6,  Ping-Pui Wong 7
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
  • 2 Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 510080.
  • 3 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Department of Otolaryngology, Head and Neck Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
  • 4 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120.
  • 5 Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 510080. Electronic address: [email protected].
  • 6 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120; Laboratory Department, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China 523000. Electronic address: [email protected].
  • 7 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA medicine, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China 510120. Electronic address: [email protected].
PMID: 36410675 DOI: 10.1016/j.phrs.2022.106558
Abstract

Dysregulated sphingolipid metabolism contributes to ER+ breast Cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic Enzyme CERK as a regulator of TAMR in breast Cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast Cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast Cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/Akt dependent cell proliferation and its driven p53/Caspase-3 mediated Apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.

Keywords

Breast cancer; CERK; Sphingolipid metabolism; Tamoxifen resistance.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13945
    99.57%, CERK Inhibitor