SCFβ-TRCP targets MTSS1 for ubiquitination-mediated destruction to regulate cancer cell proliferation and migration

Jiateng Zhong,Zhiwei Wang,Liankun Sun,Wenyi Wei,Lixin Wan,Shavali Shaik,Hiroyuki Inuzuka,Adriana E Tron

doi:10.18632/oncotarget.1446

Abstract

Metastasis suppressor 1 (MTSS1) is an important tumor suppressor protein, and loss of MTSS1 expression has been observed in several types of human cancers. Importantly, decreased MTSS1 expression is associated with more aggressive forms of breast and prostate cancers, and with poor survival rate. Currently, it remains unclear how MTSS1 is regulated in cancer cells, and whether reduced MTSS1 expression contributes to elevated cancer cell proliferation and migration. Here we report that the SCFβ-TRCP regulates MTSS1 protein stability by targeting it for ubiquitination and subsequent destruction via the 26S proteasome. Notably, depletion of either Cullin 1 or β-TRCP1 led to increased levels of MTSS1. We further demonstrated a crucial role for Ser322 in the DSGXXS degron of MTSS1 in governing SCFβ-TRCP-mediated MTSS1 degradation. Mechanistically, we defined that Casein Kinase Iδ (CKIδ) phosphorylates Ser322 to trigger MTSS1's interaction with β-TRCP for subsequent ubiquitination and degradation. Importantly, introducing wild-type MTSS1 or a non-degradable MTSS1 (S322A) into breast or prostate cancer cells with low MTSS1 expression significantly inhibited cellular proliferation and migration. Moreover, S322A-MTSS1 exhibited stronger effects in inhibiting cell proliferation and migration when compared to ectopic expression of wild-type MTSS1. Therefore, our study provides a novel molecular mechanism for the negative regulation of MTSS1 by β-TRCP in cancer cells. It further suggests that preventing MTSS1 degradation could be a possible novel strategy for clinical treatment of more aggressive breast and prostate cancers.

Highlights

Tumor metastasis is a major problem encountered during clinical anti-cancer treatments, which causes higher mortality in cancer patients [1]
To test the hypothesis that metastasis suppressor 1 (MTSS1) is a novel substrate of SCFβ, TRCP we examined whether β-TRCP directly interacts with MTSS1
We found that both exogenously expressed β-TRCP1 as well as endogenous β-TRCP1 interacts with MTSS1 (Figure 1B, 1C and Supplementary Figure S1B, S1C)

Summary

Introduction

Tumor metastasis is a major problem encountered during clinical anti-cancer treatments, which causes higher mortality in cancer patients [1]. Elucidating the underlying molecular mechanisms that cause tumor growth and metastasis will lead to the development of more effective therapies, in part by eradicating metastatic cancer cells. To this end, it has been established that for many types of human cancers, tumor cells could acquire the capability to metastasize to distant organs that results in organ failure and death [1, 2]. The mechanisms remain largely unknown, overexpression of certain oncoproteins [3] or downregulation of tumor suppressor proteins [4] have been demonstrated to play important roles in the process of tumor growth and metastasis. Findings from large cohort breast cancer clinical samples indicated that www.impactjournals.com/oncotarget

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Conclusion