Programmed cell death 10 promotes metastasis and epithelial-mesenchymal transition of hepatocellular carcinoma via PP2Ac-mediated YAP activation

Bo Sun,Yan-Rong Zhao,Lian-Yue Yang,Cong Xu,Mo-Mo Cao,Fang-Jing Zhong,Yi-Ming Li

doi:10.1038/s41419-021-04139-z

Abstract

Tumour metastasis is the main cause of postoperative tumour recurrence and mortality in patients with hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Accumulating evidence has demonstrated that programmed cell death 10 (PDCD10) plays an important role in many biological processes. However, the role of PDCD10 in HCC progression is still elusive. In this study, we aimed to explore the clinical significance and molecular function of PDCD10 in HCC. PDCD10 is significantly upregulated in HCC, which also correlates with aggressive clinicopathological characteristics and predicts poor prognosis of HCC patients after liver resection. High PDCD10 expression promotes HCC cell proliferation, migration, and invasion in vitro and tumour growth, metastasis in vivo. In addition, PDCD10 could facilitate epithelial-to-mesenchymal transition (EMT) of HCC cells. In terms of the mechanism, PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to the interaction of YAP and dephosphorylation of the YAP protein. This interaction contributes to YAP nuclear translocation and transcriptional activation. PP2Ac is necessary for PDCD10-mediated HCC progression. Knocking down PP2Ac abolished the tumour-promoting role of PDCD10 in the migration, invasion and EMT of HCC. Moreover, a PP2Ac inhibitor (LB100) could restrict tumour growth and metastasis of HCC with high PDCD10 expression. Collectively, PDCD10 promotes EMT and the progression of HCC by interacting with PP2Ac to promote YAP activation, which provides new insight into the mechanism of cancer metastasis. PDCD10 may be a potential prognostic biomarker and therapeutic target for HCC.

Highlights

Hepatocellular carcinoma (HCC) is predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide [1]
We found that Programmed cell death 10 (PDCD10) is frequently upregulated in hepatocellular carcinoma (HCC) and closely associated with aggressive clinicopathologic characteristics and poor prognosis of HCC patients after liver resection
PDCD10 mRNA was significantly upregulated in HCC tissues compared with normal liver tissues (Fig. 1A). quantitative realtime PCR (qRT-PCR) results showed that 19 of 30 (63.3%) fresh frozen HCC tissues had significantly upregulated PDCD10 expression compared with their matched adjacent non-tumorous liver tissues (ANLTs)

Summary

Introduction

Hepatocellular carcinoma (HCC) is predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide [1]. PDCD10 expression is linked to cell death, and loss of PCDC10 has been reported to increase survival and proliferation [7]. Studies from the Zhu group indicate that PDCD10 plays a tumour suppressor role in glioblastoma by inhibiting growth and invasion [8, 9]. More evidence suggests that PDCD10 acts as an oncogene in some epithelial malignant tumours, such as breast cancer [10], ovarian cancer [11], and non-small cell lung cancer [12]. Many public databases, such as Oncomine, the Gene Expression

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