Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide, and the prognosis of patients with CRC remains unsatisfactory. Basic transcription factor 3 (BTF3) is an oncogene and hazardous prognosticator in CRC. Although two distinct functional mechanisms of BTF3 in different cancer types have been reported, its role in CRC is still unclear. In this study, we aimed to molecularly characterize the oncogene BTF3 and its targets in CRC. Here, we first identified the transcriptional targets of BTF3 by applying combined RNA-Seq and ChIP-Seq analysis, identifying CHD1L as a transcriptional target of BTF3. Thereafter, we conducted immunoprecipitation (IP)-MS and E3 ubiquitin ligase analysis to identify potential interacting targets of BTF3 as a subunit of the nascent-polypeptide-associated complex (NAC). The analysis revealed that BTF3 might also inhibit E3 ubiquitin ligase HERC2-mediated p53 degradation. Finally, miRNAs targeting BTF3 were predicted and validated. Decreased miR-497-5p expression is responsible for higher levels of BTF3 post-transcriptionally. Collectively, we concluded that BTF3 is an oncogene, and there may exist a transcription factor and NAC-related proteolysis mechanism in CRC. This study provides a comprehensive basis for understanding the oncogenic mechanisms of BTF3 in CRC.
Highlights
Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide (Bray et al, 2018)
Total RNA was extracted from Basic transcription factor 3 (BTF3)-knockdown cell lines, the empty vector control cell line, and non-transfected cells using an RNeasy mini kit (Qiagen China Co., Ltd., Shanghai, China) according to the manufacturer’s protocol. cDNA was generated by reverse transcription of 1-μg aliquots of RNA using the Takara PrimeScript RT Reagent kit (Takara Biotechnology Co., Ltd., Dalian, China) according to the manufacturer’s protocol. cDNA was used for qPCR using the SYBR Premix Ex Taq kit (Takara Biotechnology Co., Ltd.) on a CFX96 instrument qPCR system (Bio Rad Laboratories, Inc., Hercules, CA, United States)
We propose that BTF3 may play an oncogenic role in CRC via HERC2mediated p53 ubiquitination and degradation
Summary
Colorectal cancer (CRC) is one of the most commonly diagnosed and leading causes of cancer mortality worldwide (Bray et al, 2018). Basic transcription factor 3 (BTF3), known as nascent-polypeptide-associated complex (NAC) beta (NACB), was reported to serve as an oncogene and convey worse prognosis in gastric. The binding of BTF3 with NACA prevents inappropriate targeting of non-secretory nascent polypeptides produced by ribosomes to the endoplasmic reticulum (Koplin et al, 2010). The NAC complex is linked to protein ubiquitination (Panasenko et al, 2009) and proteolysis (Kirstein-Miles et al, 2013) and has been reported to have a related role with BTF3, such as stabilizing BMI1 (Hu et al, 2019) and binding to the N-terminal domain of ER (Green et al, 2007). The direct targets of BTF3 as a transcription factor and part of the NAC complex, and the reason for its elevated expression in CRC, remain obscure
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