NR4A1 promotes LEF1 expression in the pathogenesis of papillary thyroid cancer

Cen Jiang,Jianli He,Jinke Cheng,Sunwang Xu,Qi Wang

doi:10.1038/s41420-022-00843-7

Abstract

The morbidity of papillary thyroid cancer (PTC) is on the rise, but its pathogenesis is still poorly understood. NR4A1 is a transcription factor primarily involving a wide range of pathophysiological responses, but its relationship with PTC malignancy remains unclear. This study demonstrates that high NR4A1 expression is strongly associated with poor survival outcomes in PTC patients. The depletion of NR4A1 significantly inhibited the proliferation of PTC cells by negating the LEF1-mediated oncogenic alteration. Mechanistically, NR4A1 directly binds to the promoter region of LEF1 and leads to crosstalk with histone acetylation and DNA demethylation to transcriptionally upregulate LEF1 expression, subsequently promoting downstream growth-related genes expressions in PTC. In the light of our findings, NR4A1 may be an emerging driving factor in PTC pathogenesis and progression.

Highlights

In the last decades, the incidence of thyroid cancer has continuously and sharply increased
We found that NR4A1 is upregulated in Papillary thyroid cancer (PTC) tissues (Fig. 1A)
The NR4A1 transcript data and matched clinicopathological features of PTC samples obtained from The Cancer Genome Atlas (TCGA) demonstrated higher expression of NR4A1 was strongly associated with shorter overall survival (OS) in PTC patients (Fig. 1C)

Summary

Introduction

The incidence of thyroid cancer has continuously and sharply increased. Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, accounting for more than 80% of all thyroid cancers [1, 2]. PTC exhibits a gentle tumor biological behavior and an excellent survival outcome, but surprisingly, the morbidity of PTC is still on the rise in recent years [3, 4]. The pathogenesis of the origin and progression of PTC is still poorly understood. Several studies have investigated the genetic alteration of PTC, including the BRAF V600E mutation and RET/PTC rearrangements [5, 6]. Despite these advances, the underlying molecular mechanism of the pathogenesis of PTC needs to be further explored

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Conclusion