Theranostics 2020; 10(10):4290-4307. doi:10.7150/thno.41008 This issue Cite

Research Paper

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

Zhijie Zhang1*, Ni Qiu1*, Jiang Yin1*, Jianlei Zhang1, Hao Liu1, Wei Guo1, Meijun Liu1, Ting Liu1, Danyang Chen1, Kai Luo1, Hongsheng Li1, Zhimin He1✉, Jinbao Liu2✉, Guopei Zheng1✉

1. Affiliated Cancer Hospital & Institute of Guangzhou Medical University; Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation; The State Key Laboratory of Respiratory; Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment”, Hengzhigang Road 78#, Guangzhou 510095, Guangdong, China.
2. Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, China.
* Equal contributors

Citation:
Zhang Z, Qiu N, Yin J, Zhang J, Liu H, Guo W, Liu M, Liu T, Chen D, Luo K, Li H, He Z, Liu J, Zheng G. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics 2020; 10(10):4290-4307. doi:10.7150/thno.41008. https://www.thno.org/v10p4290.htm
Other styles

File import instruction

Abstract

Graphic abstract

Background: 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.

Methods: SRNG overexpression was identified using microarray analysis and its clinical relevance was analyzed. To investigate the role of SRGN, we performed various in vitro and in vivo 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.

Results: 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 in vitro and in vivo by cross-talking with the transcriptional coactivator YES-associated protein (YAP) to maintain stemness in BC cells. Ectopic YAP expression restored the effects of SRGN knockdown. Inversely, YAP knockdown rescued the effects of SRGN overexpression. The secreted SRGN triggered ITGA5/FAK/CREB signaling to enhance YAP transcription. Reciprocally, YAP promoted SRGN transcription in a TEAD1-dependent manner to form a feed-forward circuit. Moreover, the YAP/RUNX1 complex promoted HDAC2 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.

Conclusions: 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.

Keywords: breast cancer, chemoresistance, SRGN, YAP, HDAC2


Citation styles

APA
Zhang, Z., Qiu, N., Yin, J., Zhang, J., Liu, H., Guo, W., Liu, M., Liu, T., Chen, D., Luo, K., Li, H., He, Z., Liu, J., Zheng, G. (2020). SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics, 10(10), 4290-4307. https://doi.org/10.7150/thno.41008.

ACS
Zhang, Z.; Qiu, N.; Yin, J.; Zhang, J.; Liu, H.; Guo, W.; Liu, M.; Liu, T.; Chen, D.; Luo, K.; Li, H.; He, Z.; Liu, J.; Zheng, G. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics 2020, 10 (10), 4290-4307. DOI: 10.7150/thno.41008.

NLM
Zhang Z, Qiu N, Yin J, Zhang J, Liu H, Guo W, Liu M, Liu T, Chen D, Luo K, Li H, He Z, Liu J, Zheng G. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics 2020; 10(10):4290-4307. doi:10.7150/thno.41008. https://www.thno.org/v10p4290.htm

CSE
Zhang Z, Qiu N, Yin J, Zhang J, Liu H, Guo W, Liu M, Liu T, Chen D, Luo K, Li H, He Z, Liu J, Zheng G. 2020. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics. 10(10):4290-4307.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image