Abstract
Diacylglycerol kinase ζ (DGKZ) is a diacylglycerol kinase that metabolizes diacylglycerol to yield phosphatidic acid, and its function in breast cancer progression remains unclear. In this study, via screening of a CRISPR-Cas9 knockout library containing lipid metabolic genes, DGKZ was identified as a potential prometastatic gene. We first confirmed that high DGKZ expression correlated with tumor progression and poor prognosis in patients. Next, knockout of DGKZ in triple-negative breast cancer cell lines were found to significantly inhibit metastatic behaviors in vitro and in vivo, whereas its overexpression increased the metastatic potential of cell lines. Mechanistic studies based on RNA sequencing and bioinformatic analysis indicated that DGKZ might regulate cell metastasis by promoting epithelial–mesenchymal transition via the transforming growth factor β (TGFβ) signaling pathway. Furthermore, we found that overexpression of DGKZ activated the TGFβ/TGFβR2/Smad3 signaling pathway by inhibiting the degradation of TGFβR2 through suppression of caveolin/lipid raft-dependent endocytosis. Moreover, the caveolin/lipid raft-dependent endocytosis of TGFβR2 was regulated by the metabolite phosphatidic acid, which might alter TGFβR2 partitioning in lipid rafts and nonlipid rafts by affecting the fluidity of the plasma membrane. These findings suggested that DGKZ is a novel promoter of metastasis and that it could be a potential prognostic indicator in patients with triple-negative breast cancer.
Highlights
Breast cancer is the most common malignant tumor that endangers women’s health worldwide, and it has attracted increasing attention due to its high morbidity and mortality [1]
DGKZ is upregulated in triple-negative breast cancer cells In our previous study, we analyzed genes related to lipid metabolism with the NCBI and GeneCards databases and constructed the CRISPR-Cas9 gene knockout library
A panel of triple-negative breast cancer (TNBC) cell lines was evaluated to examine the expression of DGKZ, and we found that the mRNA and protein expression levels of DGKZ were relatively low in TNBC cell lines with weak metastatic potential (Hs-578T and BT-549 cells), while the highly metastatic cell lines (MDA-MB-231HM and MDA-MB-231LM2) exhibited higher DGKZ expression (Fig. 1D, E)
Summary
Breast cancer is the most common malignant tumor that endangers women’s health worldwide, and it has attracted increasing attention due to its high morbidity and mortality [1]. Breast cancer with negative estrogen receptor (ER), negative progesterone receptor (PR), and negative human epidermal growth factor receptor 2 (HER2) expression is pathologically defined as triple-negative breast cancer (TNBC) [2]. It accounts for 12–17% of all breast cancers and is called refractory breast cancer because of its unclear therapeutic target, high malignancy, high risk of early recurrence and metastasis, and poor prognosis [3]. The role of most lipid molecules and enzymes in the molecular mechanism of triple-negative breast cancer metastasis remains unclear
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