Transcription factor AP-4 reactivates telomerase reverse transcriptase independently of genome alteration in non-HBV associated hepatocellular carcinoma

Cancer Heterogeneity and Plasticity 2024;1(2):0008 | https://doi.org/10.47248/chp2401020008

Original Research Open Access

Transcription factor AP-4 reactivates telomerase reverse transcriptase independently of genome alteration in non-HBV associated hepatocellular carcinoma

Huiju Lim ^1,2,† , Trevor Kwan-Hung Wu ^1,2,† , Eliana Mary Senires Suarez ^1,2 , Tiffany Ching-Yun Yu ^1,2 , Joyce Man-Fong Lee ^1,2 , Yu-Man Tsui ^1,2 , Daniel Wai-Hung Ho ^1,2 , Karen Man-Fong Sze ^1,2 , Irene Oi-Lin Ng ^1,2

1. Department of Pathology, The University of Hong Kong, Hong Kong
2. State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong

† These authors contributed equally to this work.

Correspondence: Karen Man-Fong Sze; Irene Oi-Lin Ng

Academic Editor(s): Dean Tang

Received: Sep 6, 2024 | Accepted: Nov 21, 2024 | Published: Nov 26, 2024

Cite this article: Lim H, Wu T, Suarez E, Yu T, Lee J, Tsui Y, Ho D, Sze K, Ng I. Transcription factor AP-4 reactivates telomerase reverse transcriptase independently of genome alteration in non-HBV associated hepatocellular carcinoma. Cancer Heterog Plast 2024; 1(2):0008. https://doi.org/10.47248/chp2401020008

Abstract

Recurrent genome alterations have been identified in the telomerase reverse transcriptase (TERT) promoter region, a common occurrence in various types of cancer. In addition to epigenetic alterations at the TERT promoter region, the recruitment of transcription factors to this region, which potentially drives the reactivation of TERT gene transcription in human hepatocellular carcinoma (HCC) remains unknown. In this study, using in-silico DNA binding sequence analysis at the TERT promoter and with confirmation with dual luciferase reporter and chromatin immunoprecipitation assays, we found that Transcription Factor AP-4 (TFAP4) physically interacted with the TERT promoter, driving telomerase reactivation. Furthermore, TFAP4 mRNA is upregulated in human HCCs and positively correlates with TERT mRNA expression, according to TCGA-LIHC database, our in-house clinical samples, and HCC cell lines. Interestingly, the knockdown of TFAP4 only suppressed TERT expression levels and telomere length in HCC cells which are not associated with HBV infection. Additionally, we identified that the CCCTC-binding factor (CTCF) physically interacted with the TFAP4 promoter, leading to induced TFAP4 gene transcription in HCC. Clinically, TFAP4 mRNA expression significantly correlated with TERT mRNA expression in alcohol-related HCCs, but not in HBV-associated HCCs, according to TCGA-LIHC cohort. Consistently, ethanol enhanced both TFAP4 and TERT mRNA expression in non-HBV-associated HCC cells but not HBV-associated HCC cells. In conclusion, our findings demonstrate that TFAP4 directly regulates TERT gene transcription via CTCF in non-HBV-associated HCCs. However, its role in regulating telomerase expression or activity through HBV DNA integration in HBV-associated cells might be limited.

Keywords

TERT, TFAP4, CTCF, HCC

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