Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target

Ningarhari, Massih; Caruso, Stefano; Hirsch, Théo Z.; Bayard, Quentin; Franconi, Andrea; Védie, Anne-Laure; Noblet, Bénédicte; Blanc, Jean‐Frédéric; Amaddeo, Giuliana; Ganne, Nathalie; Ziol, Marianne; Paradis, Valérie; Guettier, Catherine; Caldéraro, Julien; Morcrette, Guillaume; Kim, Youngsoo; MacLeod, A. Robert; Nault, Jean‐Charles; Rebouissou, Sandra; Zucman–Rossi, Jessica

doi:10.1016/j.jhep.2020.11.052

Cited by 67 publications

(59 citation statements)

References 47 publications

(59 reference statements)

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“…As observed in several cancers, telomeres are invariably shorter in tumors with the acquired TERT promoter mutations than those without 55,114,126,134,162,[167][168][169][170] . Earlier it was thought that the acquisition and the context at the telomere crisis during cellular transformation could be a reason for that observation in agreement with the reported reduced telomere contents in tumors with TERT modifications 54,171 .…”

Section: Tert Promoter Mutations and Telomere Lengthmentioning

confidence: 70%

“…More than half of the melanoma tumors carrying BRAF or NRAS alterations acquire TERT promoter mutations with synergistic functional consequences 125 . In hepatocellular carcinoma, TERT promoter mutations associate positively with CTNNB1 and ARID2 mutations as well as CDKN2A deletions 126 . BRAF mutations render TERT expression dependent on MAPK activation in tumors with the promoter mutations.…”

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

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Occurrence, functionality, and abundance of theTERTpromoter mutations

Rachakonda

Hoheisel

Kumar

2021

Preprint

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Telomere shortening at chromosomal ends due to the constraints of the DNA replication process acts as a tumor suppressor by restricting the replicative potential in primary cells. Cancers evade that limitation primarily through rejuvenation of telomerase via different mechanisms. Mutations within the promoter of the telomerase reverse transcriptase (TERT) gene define a definite method for the ribonucleic enzyme regeneration predominantly in cancers that arise from tissues with low rates of self-renewal. The promoter mutations cause a moderate surge in TERT transcription and telomerase rejuvenation to the levels sufficient to delay replicative senescence but not prevent bulk telomere shortening and genomic instability. Since the discovery, a staggering number of studies and publications have resolved the discrete aspects, effects, and clinical relevance of the TERT promoter mutations. Those noncoding alterations link the TERT transcription with oncogenic pathways, associate with markers of poor outcome, and define patients with reduced survivals in several cancers. In this review, we discuss the occurrence and impact of the promoter mutations and highlight the mechanism of TERT activation. We further deliberate on the foundational question of the abundance of the TERT promoter mutations and a general dearth of functional mutations within noncoding sequences as evident from pan-cancer analysis of the whole-genomes. We posit that the favorable genomic constellation within the TERT promoter may be less than a common occurrence in other noncoding functional elements and the evolutionary constraints limit the functional fraction within the human genome, hence the lack of abundant mutations outside the coding sequences.

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Section: Tert Promoter Mutations and Telomere Lengthmentioning

confidence: 70%

Section: Impact Of Tert Promoter Mutationsmentioning

confidence: 99%

Occurrence, functionality, and abundance of theTERTpromoter mutations

Rachakonda

Hoheisel

Kumar

2021

Preprint

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“…On the same line, inhibition of TERT with ASOs has been recently shown to impact on HCC growth in model animals. However, clinical translation of this result needs to ensure local delivery of the therapy to guarantee that TERT is not inhibited in tissues other than HCC [ 155 ].…”

Section: Discussionmentioning

confidence: 99%

The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective

Unfried

Sangro

Prats-Mari

et al. 2021

Cancers

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LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.

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“…Telomerase activation due to TERT promoter mutation or TERT gene amplification is one of the earliest events during HCC development [ 49 ]. The oncogenic addiction of HCC cell lines to TERT was recently identified [ 50 ], suggesting that telomerase is an actionable therapeutic target of MST-312 for treating HCC.…”

Section: Discussionmentioning

confidence: 99%

A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

Wang

Yang

2021

JPM

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Hepatocellular carcinoma (HCC) is a relatively chemo-resistant tumor. Several multi-kinase inhibitors have been approved for treating advanced HCC. However, most HCC patients are highly refractory to these drugs. Therefore, the development of more effective therapies for advanced HCC patients is urgently needed. Stathmin 1 (STMN1) is an oncoprotein that destabilizes microtubules and promotes cancer cell migration and invasion. In this study, cancer genomics data mining identified STMN1 as a prognosis biomarker and a therapeutic target for HCC. Co-expressed gene analysis indicated that STMN1 expression was positively associated with cell-cycle-related gene expression. Chemical sensitivity profiling of HCC cell lines suggested that High-STMN1-expressing HCC cells were the most sensitive to MST-312 (a telomerase inhibitor). Drug–gene connectivity mapping supported that MST-312 reversed the STMN1-co-expressed gene signature (especially BUB1B, MCM2/5/6, and TTK genes). In vitro experiments validated that MST-312 inhibited HCC cell viability and related protein expression (STMN1, BUB1B, and MCM5). In addition, overexpression of STMN1 enhanced the anticancer activity of MST-312 in HCC cells. Therefore, MST-312 can be used for treating STMN1-high expression HCC.

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Telomere length is key to hepatocellular carcinoma diversity and telomerase addiction is an actionable therapeutic target

Cited by 67 publications

References 47 publications

Occurrence, functionality, and abundance of theTERTpromoter mutations

Occurrence, functionality, and abundance of theTERTpromoter mutations

The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective

A Bioinformatics Analysis Identifies the Telomerase Inhibitor MST-312 for Treating High-STMN1-Expressing Hepatocellular Carcinoma

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