Synaptopodin‐2 suppresses metastasis of triple‐negative breast cancer via inhibition of YAP/TAZ activity

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer, with a high incidence of distant metastasis; however, the underlying mechanism for this frequent recurrence remains unclear. Herein, we show that synaptopodin-2 (SYNPO2), a putative tumour suppressor in aggressive cancer, is frequently downregulated in TNBC by methylation of the promoter of SYNPO2. Low expression levels of SYNPO2 correlated significantly with 5-year metastatic relapse, and predicted poorer prognosis in breast cancer patients. Reintroduction of SYNPO2 inhibited the invasion and spontaneous metastasis of TNBC cells in vivo. Strikingly, downregulation of SYNPO2 is essential for the maintenance of stem cell-like properties in TNBC cells, leading to efficient distant colonization and metastasis outgrowth. Moreover, we demonstrate that SYNPO2 inhibits the activities of YAP and TAZ by stabilizing LATS2 protein, and transduction of YAP-S127A abrogates the repressive role of SYNPO2 in metastasis. Finally, immunohistochemical (IHC) analysis of breast cancer patient specimens indicated that the SYNPO2-LATS2-YAP axis is clinically relevant. These findings uncover a suppressive role of SYNPO2 in TNBC metastasis via inhibition of YAP/TAZ, and suggest that SYNPO2 might provide a potential prognosis marker and novel therapeutic strategy.

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

“…Another study published at that time also found that activation of YAP, in this case through loss of Leukemia Inhibitory Factor Receptor (LIFR), promoted metastatic colonization of breast cancer cells [ 117 ]. Since these initial studies, several others have directly implicated YAP, TAZ, or TEADs in metastasis of numerous cancer types, including melanoma [ 118 ], lung cancer [ 119 , 120 , 121 ], breast cancer [ 86 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ], cholangiocarcinoma [ 82 , 129 ], gastric cancer [ 130 , 131 , 132 , 133 ], ovarian cancer [ 134 ], colorectal cancer [ 135 , 136 , 137 ], and oral squamous cell carcinoma [ 101 ]. Conversely, LATS1 overexpression reduces gastric cancer metastasis [ 138 ].…”

“…As with EMT, YAP/TAZ-mediated migration and invasion is dependent upon TEADs. Importantly, several studies that demonstrate YAP or TAZ-dependent metastasis formation also showed that YAP or TAZ promotes the migration and/or invasion of the cancer cells [ 82 , 86 , 118 , 120 , 125 , 128 , 129 , 132 , 133 , 135 , 136 , 137 ]. Although the YAP/TAZ target genes responsible for enhanced tumor cell migration and invasion are likely numerous, context-dependent, and cancer-type specific, some have been clearly identified.…”

The crosstalk between AXL and YAP promotes tumor progression through STAT3 activation in head and neck squamous cell carcinoma

“…leading to YAP cytoplasmic retention and degradation. YAP S127A , an activated mutant, 24 was constructed to avoid LATS1 inhibition and enhance CCN2-promoter activity ( Figure S7). Our result showed that Gas6 increased CCN2-promoter activities in Vector groups and YAP WT groups.…”

Vitamin C Inhibits Triple-Negative Breast Cancer Metastasis by Affecting the Expression of YAP1 and Synaptopodin 2

“…Both proteins are key players in the Hippo pathway and have known functions in metastasis formation, consistently with the changes we observed in cultured TNBC cells and xenografts after vitamin C treatment. Activation of YAP1 promotes F-actin assembly and lamellipodia formation, which are essential to cell mobility and invasion [19]. Our results show that vitamin C treatment downregulates the expression of YAP1 and upregulates that of SYNPO2, which further inhibits the activity of YAP1.…”

“…SYNPO2 has been found to suppress metastasis by inhibiting the activity of the transcriptional coactivator YAP1, also known as yes-associated protein 1 [19]. As a key regulator in the Hippo pathway, YAP1 promotes focal adhesion formation and metastasis [20].…”