Suppression of PROX1‐mediated TERT expression in hepatitis B viral hepatocellular carcinoma. Issue 12 (27th September 2018)

• Record Type: Journal Article
• Authors: Kim, Young‐Joo; Yoo, Jeong Eun; Jeon, Youngsic; Chong, Jae Uk; Choi, Gi Hong; Song, Dae‐Geun; Jung, Sang Hoon; Oh, Bong‐Kyeong; Park, Young Nyun
• Is Part Of: International journal of cancer. Volume 143:Issue 12(2018)
• Page Start: 3155
• Page End: 3168
• Publication Date: 2018-09-27
• Subjects: TERT promoter mutation -- B viral hepatocellular carcinoma -- PROX1 -- transcription factor -- HBx; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.31731
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Somatic mutations in the telomerase reverse transcriptase ( TERT ) promoter are related to telomerase activation and frequently occur at two hot spots located at −124 and −146 bp relative to the start codon in various cancers. Here, we investigated the occurrence and implications of genetic alterations in the TERT promoter in hepatitis B viral hepatocellular carcinoma (B viral HCC). TERT promoter mutations, especially −124C>T, clearly enhanced transcriptional activity in HCC cell lines. In contrast, TERT mRNA expression was lower in B viral HCC patients with TERT promoter mutations than in those without. We identified prospero homeobox protein 1 (PROX1) as a novel transcriptional activator of TERT ; this protein was shown to have particularly strong binding affinity for the mutant TERT promoter. However, stable expression of the hepatitis B virus X (HBx) protein inhibited PROX1‐mediated TERT expression in vitro. Our data suggest that TERT promoter mutations can enhance the promoter activity in HCC cell lines expressing PROX1 but are not the predominant mechanism of TERT upregulation in B viral HCC patients, based on the inhibition of PROX1‐dependent transcriptional activation by HBx. Abstract : What's new? Telomerase activation and cell immortalization are critical steps in cancer development and progression and are associated with mutations in the telomerase reverse transcriptase ( TERT ) gene. Here, in hepatocellular carcinoma (HCC) cells, the transcription factor prospero homeobox protein 1 (PROX1) was found to regulate the TERT gene by binding to the mutated TERT promoter with a consensus ETS/TCF‐binding sequence. Hepatitis B virus X protein (HBx) inhibited PROX1 binding to the TERT promoter, resulting in TERT mRNA downregulation. The findings suggest that in B viral HCC, mutations enhancing TERT promoter activity in PROX1‐expressing cells are not the primary mechanism behind TERT upregulation.