SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression

Abstract

<b>Background</b>: Chemoresistance is a significant obstacle to the effective treatment of breast cancer (BC), resulting in more aggressive behavior and worse clinical outcome. The molecular mechanisms underlying breast cancer chemoresistance remain unclear. Our microarray analysis had identified the overexpression of a small molecular glycoprotein serglycin (SRGN) in multidrug-resistant BC cells. Here, we aimed to investigate the role of SRGN in chemoresistance of breast cancer and elucidate the underlying mechanisms. <b>Methods</b>: SRNG overexpression was identified using microarray analysis and its clinical relevance was analyzed. To investigate the role of SRGN, we performed various <i>in vitro</i> and <i>in vivo</i> studies, as well as characterization of serum and tissue samples from BC patients. Chemosensitivity measurement, gene expression interference, immunofluorescence staining, mammosphere assay, flow cytometry analysis, luciferase reporter assay, ChIP-qPCR, coimmunoprecipitation, and immunohistochemistry were performed to explore the potential functions and mechanisms of SRGN. <b>Results</b>: We confirmed overexpression of SRGN in chemoresistant BC cells and in serum and tissue samples from BC patients with poor response to chemotherapy. SRGN specifically predicted poor prognosis in BC patients receiving chemotherapy. Mechanistically, SRGN promoted chemoresistance both <i>in vitro</i> and <i>in vivo</i> by cross-talking with the transcriptional coactivator YES-associated protein (YAP) to maintain stemness in BC cells. Ectopic YAP expression restored the effects of <i>SRGN</i> knockdown. Inversely, YAP knockdown rescued the effects of <i>SRGN</i> overexpression. The secreted SRGN triggered ITGA5/FAK/CREB signaling to enhance <i>YAP</i> transcription. Reciprocally, YAP promoted <i>SRGN</i> transcription in a TEAD1-dependent manner to form a feed-forward circuit. Moreover, the YAP/RUNX1 complex promoted <i>HDAC2</i> transcription to induce chemoresistance and stemness in BC cells. Importantly, the SRGN levels were positively correlated with the YAP and HDAC2 levels in chemoresistant BC tissues. YAP and HDAC2 acted downstream of SRNG and correlated with poor outcomes of BC patients receiving chemotherapy. <b>Conclusions</b>: Our findings clarify the roles and mechanisms of SRGN in mediating chemoresistance in breast cancer and suggest its use a potential biomarker for chemotherapeutic response. We believe that novel therapeutic strategies for breast cancer can be designed by targeting the signaling mediated by the crosstalk between SRGN and YAP.