Exploring the Role and Mechanism of pAMPKα-Mediated Dysregulation of Brf1 and RNA Pol III Genes.

Teng Wu,Mingen Lin,Shuai Li,Lihong Yu,Ting Dai,Lei Lu,Shuping Zhong,Dongkun Zhang,Liling Zheng,Fenghai Yu,Jayeeta Ghose

doi:10.1155/2021/5554932

Abstract

TF IIB-related factor 1 (Brf1) is a key transcription factor of RNA polymerase III (Pol III) genes. Our early studies have demonstrated that Brf1 and Pol III genes are epigenetically modulated by histone H3 phosphorylation. Here, we have further investigated the relationship of the abnormal expression of Brf1 with a high level of phosphorylated AMPKα (pAMPKα) and explored the role and molecular mechanism of pAMPKα-mediated dysregulation of Brf1 and Pol III genes in lung cancer. Brf1 is significantly overexpressed in lung cancer cases. The cases with high Brf1 expression display short overall survival times. Elevation of Brf1 expression is accompanied by a high level of pAMPKα. Brf1 and pAMPKα colocalize in nuclei. Further analysis indicates that the carcinogen MNNG induces pAMPKα to upregulate Brf1 expression, resulting in the enhancement of Pol III transcription. In contrast, inhibiting pAMPKα decreases cellular levels of Brf1, resulting in the reduction of Pol III gene transcription to attenuate the rates of cell proliferation and colony formation of lung cancer cells. These outcomes demonstrate that high Brf1 expression reveals a worse prognosis in lung cancer patients. pAMPKα-mediated dysregulation of Brf1 and Pol III genes plays important roles in cell proliferation, colony formation, and tumor development of lung cancer. Brf1 may be a biomarker for establishing the prognosis of lung cancer. It is a new mechanism that pAMPKα mediates dysregulation of Brf1 and Pol III genes to promote lung cancer development.

Highlights

Lung cancer is a common malignant tumor
The result indicates that a strong signal of Brf1 was detected in tumor foci tissue (Figure 1(a), left panel), while a very weak reaction of Brf1 with its antibody was observed in paracarcinoma tissue (Figure 1(a), right panel)
The results reveal that MNNG treatment significantly promotes colony formation of the cells, compared to the cells without MNNG treatment (Figure 9(c)), whereas inhibiting AMPKα dramatically decreases the rate of colony formation, which displays a significant difference between with and without S7306 treatment (Figure 9(d))

Summary

Introduction

Lung cancer is a common malignant tumor. The incidence of lung cancer in China has increased [1, 2]. It is a malignant tumor with the highest morbidity and mortality in the country. SCLC is a heterogeneous neoplastic disease characterized by aggressiveness, rapid growth of cancer cells, and easy metastases [5], while NSCLC is a kind of epithelial malignant disease apart from SCLC. Lung carcinogenesis involves multiple mechanisms: oncogene activation, such as K-Ras [6]; inactivation of tumor suppressor genes (LKB1) [7]; epidermal growth factor receptor (EGFR) mutation and amplification [8]; inhibition of immune system activity [9, 10]; and epigenetic alterations (DNA methylation, histone tail modifications, and small RNAs) [11].

Methods

Results

Discussion

Conclusion