MTBP enhances the activation of transcription factor ETS-1 and promotes the proliferation of hepatocellular carcinoma cells

Hongbo Wang; Fang Chu; Li Zhijie; Qian Bi; Li Lixin; Yunlong Zhuang; Zhang Xiaofeng; Xiaofeng Niu; Dali Zhang; He Xi; Bo-An Li

doi:10.3389/fonc.2022.985082

MTBP enhances the activation of transcription factor ETS-1 and promotes the proliferation of hepatocellular carcinoma cells

Front Oncol. 2022 Aug 29:12:985082. doi: 10.3389/fonc.2022.985082. eCollection 2022.

Authors

Hongbo Wang¹, Fang Chu², Li Zhijie¹, Qian Bi³, Li Lixin¹, Yunlong Zhuang¹, Zhang Xiaofeng¹, Xiaofeng Niu¹, Dali Zhang¹, He Xi¹, Bo-An Li⁴

Affiliations

¹ Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
² Department of Emergency, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.
³ Endoscopy Center, Department of Hepatology, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.
⁴ Clinical Laboratory, The Fifth Medical Center of Chinese People's Liberation Army General Hospital, Beijing, China.

Abstract

Increasing evidence indicates that the oncoprotein murine double minute (MDM2) binding protein (MTBP) can be considered a pro-oncogene of human malignancies; however, its function and mechanisms in hepatocellular carcinoma (HCC) are still not clear. In the present work, our results demonstrate that MTBP could function as a co-activator of transcription factor E26 transformation-specific sequence (ETS-1), which plays an important role in HCC cell proliferation and/or metastasis and promotes proliferation of HCC cells. Using luciferase and real-time polymerase chain reaction (qPCR) assays, MTBP was found to enhance the transcription factor activation of ETS-1. The results from chromatin co-immunoprecipitation showed that MTBP enhanced the recruitment of ETS-1 to its downstream gene's (mmp1's) promoter region with ETS-1 binding sites. In cellular and nude mice models, overexpression of MTBP was shown to promote the proliferation of MHCC97-L cells with low endogenous MTBP levels, whereas the knockdown of MTBP led to inhibition of the proliferation of MHCC97-H cells that possessed high endogenous levels of MTBP. The effect of MTBP on ETS-1 was confirmed in the clinical specimens; the expression of MTBP was positively correlated with the downstream genes of ETS-1, mmp3, mmp9, and uPA. Therefore, by establishing the role of MTBP as a novel co-activator of ETS-1, this work expands our knowledge of MTBP or ETS-1 and helps to provide new ideas concerning HCC-related research.

Keywords: E26 transformation specific sequence 1; Hepatocellular carcinoma; MDM2 binding protein; proliferation; protein interaction; transcription factor activation.