RASSF1A inhibits PDGFB-driven malignant phenotypes of nasopharyngeal carcinoma cells in a YAP1-dependent manner

Ying-Ying Liang,Ya-Wei Yuan,Li-Li Jiang,Xu-Bin Deng,Xian-Tao Lin,Zhi-Wen Mo,Xiao-Ting Huang,Muy-Teck Teh

doi:10.1038/s41419-020-03054-z

Abstract

Nasopharyngeal carcinoma (NPC) is a highly aggressive tumor characterized by distant metastasis. Deletion or down-regulation of the tumor suppressor protein ras-association domain family protein1 isoform A (RASSF1A) has been confirmed to be a key event in NPC progression; however, little is known about the effects or underlying mechanism of RASSF1A on the malignant phenotype. In the present study, we observed that RASSF1A expression inhibited the malignant phenotypes of NPC cells. Stable silencing of RASSF1A in NPC cell lines induced self-renewal properties and tumorigenicity in vivo/in vitro and the acquisition of an invasive phenotype in vitro. Mechanistically, RASSF1A inactivated Yes-associated Protein 1 (YAP1), a transcriptional coactivator, through actin remodeling, which further contributed to Platelet Derived Growth Factor Subunit B (PDGFB) transcription inhibition. Treatment with ectopic PDGFB partially increased the malignancy of NPC cells with transient knockdown of YAP1. Collectively, these findings suggest that RASSF1A inhibits malignant phenotypes by repressing PDGFB expression in a YAP1-dependent manner. PDGFB may serve as a potential interest of therapeutic regulators in patients with metastatic NPC.

Highlights

Ras-association domain family protein[1] isoform A (RASSF1A) is a well-known tumor suppressor protein inactivated by a combination of genetic and epigenetic mechanisms in various human cancers
Acting as a downstream effector of the Hippo pathway, Yes-associated Protein 1 (YAP1) has been identified as a proto-oncogene, as it acts by binding to the transcription factor TEAD1–4 (TEA domain family member, the major partner of YAP1 in its function in the Hippo pathway) and subsequently activates the transcription of genes involved in cell survival/proliferation and suppresses the transcription of apoptotic genes such as cMyc, OCT4, Cysteine-rich angiogenic inducer 61 (CYR61), and CTGF12–14
We demonstrated that ras-association domain family protein1 isoform A (RASSF1A) impairs malignant phenotypes by inhibiting YAP1mediated expression of Platelet Derived Growth Factor Subunit B (PDGFB) during multiple steps of Nasopharyngeal carcinoma (NPC) carcinogenesis

Summary

Introduction

Ras-association domain family protein[1] isoform A (RASSF1A) is a well-known tumor suppressor protein inactivated by a combination of genetic and epigenetic mechanisms in various human cancers. RASSF1A is located on chromosome 3p21.3 and is downregulated in human tumor cells most frequently by promoter methylation and infrequently by mutation or deletion[1]. Overexpression of RASSF1A significantly inhibits cell proliferation and induces apoptosis by inhibiting the oncogenic functions of YAP111. Acting as a downstream effector of the Hippo pathway, YAP1 has been identified as a proto-oncogene, as it acts by binding to the transcription factor TEAD1–4 (TEA domain family member, the major partner of YAP1 in its function in the Hippo pathway) and subsequently activates the transcription of genes involved in cell survival/proliferation and suppresses the transcription of apoptotic genes such as cMyc, OCT4, CYR61, and CTGF12–14

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