SIRT7 antagonizes TGF-\u03b2 signaling and inhibits breast cancer metastasis

Xiaolong Tang,Baohua Liu,Mingyan Zhou,Ni Xie,Wei-Guo Zhu,Fanbiao Meng,Qingyang Xu,Zuojun Liu,Xinyue Cao,Minxian Qian,Lei Shi

doi:10.1038/s41467-017-00396-9

Abstract

Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy.

Highlights

Distant metastasis is the main cause of breast cancer-related death; effective therapeutic strategies targeting metastasis are still scarce
Transforming growth factor-β (TGF-β) is a key regulator of epithelial-to-mesenchymal transition (EMT): extracellular TGF-β signal is transduced through the activation of TGF-β receptors (TGFβR) and subsequent phosphorylation of receptor-activated SMADs (R-SMADs), which form heterotrimeric complex with SMAD4
500 μm. h Scatter plot showing lung metastatic nodules from animals injected with empty vector control (EV) or OESIRT7 cells (n = 13 and 10, respectively). i Representative images of lung and H&E-stained lung sections from spontaneous metastases generated in polyomavirus middle T antigen (PyMT) or PyMT; Sirt7 transgenic mice (Sirt7tg) mice after doxycycline feeding

Summary

Introduction

Distant metastasis is the main cause of breast cancer-related death; effective therapeutic strategies targeting metastasis are still scarce. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, providing an effective anti-metastatic therapeutic strategy. An epithelial-to-mesenchymal transition (EMT) program underlies the dynamic cellular heterogeneity during metastasis[4], whereby epithelial cells gradually lose polarity and adhesion capacity but acquire mesenchymal traits, i.e., motility and invasiveness[5] Such spatial and temporal heterogeneity dictates one of the biggest challenges of targeted breast cancer therapy, which mainly rely on the histological and molecular characteristics of primary tumors[6, 7]. SMAD4, as a central transducer of TGF-β signaling, is highly mutated during clonal evolution and metastases in colorectal and pancreatic cancers[14, 15] Such loss-of-function mutations are rare in invasive breast cancers and SMAD4 deficiency rather inhibits metastasis[16]. Data are shown as mean ± S.E.M. and representative of two independent experiments

Methods

Results

Conclusion