Interplay between c-Src and the APC/C co-activator Cdh1 regulates mammary tumorigenesis

Tao Han,Mengyu Xie,Su Jung Song,Ming Chen,Lixin Wan,Amer A Beg,Xiu Yin,Shulong Jiang,Qing Yin,Hong Zheng,Margaret R Little,Pier Paolo Pandolfi

doi:10.1038/s41467-019-11618-7

Abstract

The Anaphase Promoting Complex (APC) coactivator Cdh1 drives proper cell cycle progression and is implicated in the suppression of tumorigenesis. However, it remains elusive how Cdh1 restrains cancer progression and how tumor cells escape the inhibition of Cdh1. Here we report that Cdh1 suppresses the kinase activity of c-Src in an APC-independent manner. Depleting Cdh1 accelerates breast cancer cell proliferation and cooperates with PTEN loss to promote breast tumor progression in mice. Hyperactive c-Src, on the other hand, reciprocally inhibits the ubiquitin E3 ligase activity of APCCdh1 through direct phosphorylation of Cdh1 at its N-terminus, which disrupts the interaction between Cdh1 and the APC core complex. Furthermore, pharmacological inhibition of c-Src restores APCCdh1 tumor suppressor function to repress a panel of APCCdh1 oncogenic substrates. Our findings reveal a reciprocal feedback circuit of Cdh1 and c-Src in the crosstalk between the cell cycle machinery and the c-Src signaling pathway.

Highlights

The Anaphase Promoting Complex (APC) coactivator Cdh[1] drives proper cell cycle progression and is implicated in the suppression of tumorigenesis
Dysregulation of the cell cycle machinery plays an important role in driving breast carcinogenesis[23]
Cdh[1] protein level oscillates across the cell cycle[28], and we found that p-Y419-Src level decreased when Cdh[1] was accumulated in MDA-MB-231 and T47D cells in synchronization experiments (Fig. 1k and Supplementary Fig. 1n–p)

Summary

Introduction

The Anaphase Promoting Complex (APC) coactivator Cdh[1] drives proper cell cycle progression and is implicated in the suppression of tumorigenesis It remains elusive how Cdh[1] restrains cancer progression and how tumor cells escape the inhibition of Cdh[1]. In addition to its function as the APC coactivator, Cdh[1] has been shown to activate the Smurf[1] E3 ligase in osteoblasts[10] and to suppress BRAF kinase activity in melanoma cells[8] in an APC-independent manner These findings indicate that Cdh[1] may possess unique characteristics in cell cycle phases other than M and G1, and more importantly, in malignant settings where APCCdh[1] is largely inhibited[11]. Pharmacologically inhibiting Src restores the tumor suppressor function of APCCdh[1], and synergistically suppresses the growth of triple negative breast cancer cells with MEK inhibition

Methods

Results

Conclusion