PRDM16 Inhibits Cell Proliferation and Migration via Epithelial-to-Mesenchymal Transition by Directly Targeting Pyruvate Carboxylase in Papillary Thyroid Cancer

Wan-Lin Liu,Qing Guan,Wen-Jun Wei,Duan-Shu Li,Jun Xiang,Tian Liao,Yu Wang,Qing-Hai Ji,Ben Ma,Jia-Qian Hu,Duo Wen,Wei-Bo Xu

doi:10.3389/fcell.2021.723777

Abstract

PRDM16 (known as MEL1), a member of the PR domain zinc finger family, has been implicated in multiple biological processes, including cancers. It is not clear yet whether PRDM16 is involved in tumor progress of papillary thyroid cancer (PTC). We identified the PRDM16 expression level in PTC tissues by qRT-PCR and analyzed its relationship with clinical characteristics in both Fudan University Shanghai Cancer Center (FUSCC) and TCGA cohorts. We tested the function of PRDM16 in PTC cells both in vivo and in vitro. We found a direct downstream target of PRDM16, pyruvate carboxylase (PC), by RNA-sequencing, rescue experiments, luciferase assay, and chromatin immunoprecipitation assay. PRDM16 was downregulated in papillary thyroid cancer tissues and was significantly related with lymph node metastases and extrathyroidal extension in both FUSCC and TCGA cohorts. Overexpression of PRDM16 could attenuate proliferation and migration of PTC cells via inhibiting the epithelial-to-mesenchymal transition process. PC was upregulated in papillary thyroid cancer tissues. Knockdown of PC could inhibit proliferation and migration in TPC-1 and K1 cells. The repression effect on cell proliferation and migration from PRDM16 was PC dependent. PRDM16 could directly bind to the PC promoter and inhibit its expression at the transcription level. Moreover, the mRNA expression level of PRDM16 and PC was negatively related in human PTC tissues. In conclusion, PRDM16 exhibited an antitumor effect and EMT inhibition function in PTC by directly binding with the PC promoter. PRDM16 may be a novel therapeutic target in papillary thyroid cancer.

Highlights

Thyroid cancer is the most common type of endocrine malignancy
To evaluate PRDM16 expression in papillary thyroid cancer (PTC) tissue, qRT-PCR and IHC were performed in 110 PTC and matched adjacent thyroid tissue specimens from the Fudan University Shanghai Cancer Center (FUSCC) cohort
Low PRDM16 expression was significantly associated with ETE and lymph node metastases (LNM) in both the FUSCC and The Cancer Genome Atlas (TCGA) cohorts, showing a lower expression level of PRDM16 in PTC with aggressive

Summary

Introduction

Thyroid cancer is the most common type of endocrine malignancy. Since the 1970s, its incidence has increased threefold over the past three decades all over the world (Chen et al, 2009). Worldwide trends in thyroid cancer incidence have been largely driven by an increase in PTC, followed by follicular, medullar, and anaplastic histological subtypes (Kitahara and Sosa, 2016). Prognostic factors of recurrence for PTC include age at diagnosis, histological subtypes, extrathyroidal extension (ETE), lymph node metastases (LNM), and tumornode-metastasis (TNM) stage (Leboulleux et al, 2005). The BRAFV600E gene mutation is widely demonstrated to be associated with ETE, LNM, recurrence, and mortality (Caronia et al, 2011; Cancer Genome Atlas Research Network, 2014; Liu et al, 2014; Xing et al, 2015) and are considered to be a potential target for treatment of PTC (Cabanillas et al, 2015; Falchook et al, 2015). The underlying factors and mechanisms for the aggressiveness of PTC remain unclear

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Conclusion