\u03b2-Trcp and CK1\u03b4-mediated degradation of LZTS2 activates PI3K/AKT signaling to drive tumorigenesis and metastasis in hepatocellular carcinoma

Yanwei Lu,Kunyu Yang,Gang Wu,Xudong Li,Hongli Liu,Jun Xue,Xiaorong Dong,Shuangbing Xu,Zhen Zeng,Tao Zhang

doi:10.1038/s41388-020-01596-2

Yanwei Lu, Kunyu Yang + Show 8 more

Open Access

https://doi.org/10.1038/s41388-020-01596-2

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Abstract

Distant metastasis is the leading cause of treatment failure in patients with hepatocellular carcinoma (HCC). However, the underlying mechanisms have not been fully elucidated. Here, we report that Leucine zipper tumor suppressor 2 (LZTS2) is downregulated and correlated with poor prognosis in HCC. Furthermore, we provide evidence that LZTS2 associates with p85 to inhibit the activation of PI3K/AKT signaling and impairs HCC tumorigenesis and metastasis in vitro and in vivo. Moreover, we identify LZTS2 as a bona fide substrate of the E3 ligase β-Trcp and protein kinase CK1δ, which are responsible for the ubiquitination and degradation of LZTS2. Importantly, we show that the β-Trcp and CK1δ-mediated degradation of LZTS2 promotes HCC progression and metastasis by activating PI3K/AKT signaling. Collectively, our study not only illustrates the roles of LZTS2 in regulating HCC tumorigenesis and metastasis but also reveals a novel posttranslational modification of LZTS2 by β-Trcp and CK1δ, indicating that the β-Trcp/CK1δ/LZTS2/PI3K axis may be a novel oncogenic driver involved in HCC progression and metastasis.

Highlights

Hepatocellular carcinoma (HCC), the most common histological type of primary liver cancer, is the third leading cause of cancer-related death worldwide [1]
For the first time, we reveal the roles of Leucine zipper tumor suppressor 2 (LZTS2) in impairing tumorigenesis and metastasis in hepatocellular carcinoma (HCC) in a p85dependent manner
As the proper phosphorylation of substrate proteins by special protein kinases is critical for recognition and binding by β-transducin repeat-containing protein (β-Trcp), our results identified CK1δ as the upstream kinase that is involved in the β-Trcp-mediated ubiquitination of LZTS2

Summary

Introduction

Hepatocellular carcinoma (HCC), the most common histological type of primary liver cancer, is the third leading cause of cancer-related death worldwide [1]. Tumor suppressor proteins FOXN2 and Mxi are ubiquitination substrates of the E3 ligase β-Trcp, and this ubiquitination modification is involved in lung cancer radioresistance [17, 18], supporting the role of β-Trcp in DNA damage repair. Our previous study demonstrated that LZTS2 inhibits the activation of the PI3K/AKT signaling pathway to impair tumorigenesis and radioresistance in nasopharyngeal carcinoma [24]. These findings support the notion that LZTS2 acts as a tumor suppressor protein. We further uncover that the E3 ubiquitin ligase β-Trcp and the protein kinase CK1δmediated destruction of LZTS2 contribute to tumorigenesis and metastasis by activating the PI3K/AKT signaling pathway in HCC. Our study reveals a previously unknown antimetastatic role and a novel posttranslational modification of LZTS2, indicating that LZTS2 may be an attractive therapeutic target for HCC

Results

Discussion

Materials and methods

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