Yap-Hippo Signaling Activates Mitochondrial Protection and Sustains Breast Cancer Viability under Hypoxic Stress.

Chen Shi,Changkuo Guo,Jian Tie,Siyuan Zhang,Yun-Dai Chen

doi:10.1155/2021/5212721

Abstract

Yes-associated protein (Yap) is a transcriptional regulator that upregulates oncogenes and downregulates tumor repressor genes. In this study, we analyzed protein expression, RNA transcription, and signaling pathways to determine the function and mechanism of Yap in breast cancer survival during hypoxic stress. Yap transcription was drastically upregulated by hypoxia in a time-dependent manner. siRNA-mediated Yap knockdown attenuated breast cancer viability and impaired cell proliferation under hypoxic conditions. Yap knockdown induced mitochondrial stress, including mitochondrial membrane potential reduction, mitochondrial oxidative stress, and ATP exhaustion after exposure to hypoxia. It also repressed mitochondrial protective systems, including mitophagy and mitochondrial fusion upon exposure to hypoxia. Finally, our data showed that Yap knockdown suppresses MCF-7 cell migration by inhibiting F-actin transcription and promoting lamellipodium degradation under hypoxic stress. Taken together, Yap maintenance of mitochondrial function and activation of F-actin/lamellipodium signaling is required for breast cancer survival, migration, and proliferation under hypoxic stress.

Highlights

Breast cancer is the most commonly diagnosed cancer in women, with an estimated 268,600 newly diagnosed women with invasive disease in 2019 in the United States [1]
Loss of Yes-associated protein (Yap) induced a decline in mitochondrial ATP production and caused intracellular calcium overload, resulting into cancer cell mobilization impairment
Based on these studies [7], we questioned whether mitochondrial dysfunction occurred downstream as a result of Yap knockdown

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer in women, with an estimated 268,600 newly diagnosed women with invasive disease in 2019 in the United States [1]. Yes-associated protein (Yap) was originally reported as a transcriptional regulator that upregulates the transcription of oncogenes and reduces the levels of tumor suppressors. After stimulation by hypoxia and inflammation, Yap is phosphorylated at Ser127 [5] and translocates into the nucleus, where it regulates gene expression related to tumor development with the help of transcriptional coactivators with a PDZ-binding motif (TAZ) [6]. We found that Yap inhibited JNK phosphorylation and sustained the levels of mitochondria-generated ATP, favoring cancer migration and mobilization. In addition to liver cancer, abundant expression of Yap modulates the activity of macrophage stimulating 4 (MST4) kinase and is associated with gastric tumorigenesis [6]. The level of intracellular total Yap rather than its phosphorylation status has been used as a prognostic biomarker [9].

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