Protein tyrosine phosphatase receptor type D gene promotes radiosensitivity via STAT3 dephosphorylation in nasopharyngeal carcinoma

Yanling Lin,Dehua Wu,Yujiang Li,Yuting Chen,Yingtong Zhou,Yiming Lei,Longmei Cai,Wenxiao Luo,Jinrong Liao,Xiaohan Zhou,Kaifan Yang,Lingzhi Wang,Yanting Zhang

doi:10.1038/s41388-021-01768-8

Abstract

Radiotherapy is essential to the treatment of nasopharyngeal carcinoma (NPC) and acquired or innate resistance to this therapeutic modality is a major clinical problem. However, the underlying molecular mechanisms in the radiation resistance in NPC are not fully understood. Here, we reanalyzed the microarray data from public databases and identified the protein tyrosine phosphatase receptor type D (PTPRD) as a candidate gene. We found that PTPRD was downregulated in clinical NPC tissues and NPC cell lines with its promoter hypermethylated. Functional assays revealed that PTPRD overexpression sensitized NPC to radiation in vitro and in vivo. Importantly, miR-454-3p directly targets PTPRD to inhibit its expression and biological effect. Interestingly, mechanistic analyses indicate that PTPRD directly dephosphorylates STAT3 to enhance Autophagy-Related 5 (ATG5) transcription, resulting in triggering radiation-induced autophagy. The immunohistochemical staining of 107 NPC revealed that low PTPRD and high p-STAT3 levels predicted poor clinical outcome. Overall, we showed that PTPRD promotes radiosensitivity by triggering radiation-induced autophagy via the dephosphorylation of STAT3, thus providing a potentially useful predictive biomarker for NPC radiosensitivity and drug target for NPC radiosensitization.

Highlights

Nasopharyngeal carcinoma (NPC), a malignancy derived from the nasopharyngeal epithelium, has a high prevalence in Southern China and Southeast Asia [1]
We demonstrated that phosphatase receptor type D (PTPRD) overexpression sensitizes NPC cells to radiotherapy by regulating autophagy-related cell death through the direct targeting of STAT3, whereas the reactivation of STAT3 abrogated the effects of PTPRD overexpression
Based on the two microarray data sets, we identified PTPRD as a candidate gene that was downregulated by miRNA and hypermethylated in its promoter, leading to epigenetic silencing in NPC

Summary

Introduction

Nasopharyngeal carcinoma (NPC), a malignancy derived from the nasopharyngeal epithelium, has a high prevalence in Southern China and Southeast Asia [1]. We investigated the mechanism underlying NPC radiosensitivity, identified a novel substrate, and biological function of PTPRD, and revealed a targetable pathway to sensitize NPC to radiation. 143 common genes were identified to be downregulated by the miRNA and hypermethylated in methylation microarrays (Fig. 1A). Top six differentially expressed genes were identified in five NPC, and five noncancerous nasopharyngeal samples and confirmed using RTqPCR. They included CYLD, PTPRD, FRZB, CUL3, KLF11, and TFAP2B (Fig. 1B). The methylation levels of PTPRD were significantly upregulated in NPC tissues compared with normal tissues, indicating that PTPRD is hypermethylated in NPC Following DAC treatment, PTPRD methylation levels were clearly decreased in the NPC cell lines (Fig. 1H), and PTPRD mRNA levels were substantially increased (Fig. 1I)

Results

Discussion

Materials and methods

Compliance with ethical standards