GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression

Yuan, Xiaotian; Mu, Ninni; Wang, Na; Strååt, Klas; Sofiadis, Anastasios; Guo, Yanxia; Stenman, Adam; Li, Kailin; Cheng, Guanghui; Zhang, Lu; Kong, Feng; Ekblad, Lars; Wennerberg, Johan; Nilsson, Inga-Lena; Juhlin, Carl Christofer; Larsson, Catharina; Xu, Dawei

doi:10.1038/s41388-018-0483-x

Cited by 44 publications

(85 citation statements)

References 47 publications

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“…Despite significantly diminished TERT expression in mutant TERT promotercarrying BC cells upon GABPA knockdown, these cells exhibited augmented proliferation, stemness, and invasive capacities, indicating that GABPA itself has a predominant role in suppressing BC aggressive state independently of TERT expression. This same scenario was recently observed in TC cells, too [46]. However, Mancini et al [25] showed that mutant TERT promoter-harboring glioblastoma cells exhibited decreased TERT expression coupled with impaired proliferation upon GABPB1L depletion within 48 h and longer incubation time triggered telomere shortening/dysfunction and attenuated tumorigenic ability of these cells.…”

Section: Discussionsupporting

confidence: 66%

GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer

Guo

Yuan

et al. 2019

Cell Death Differ

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TERT promoter mutations occur in the majority of glioblastoma, bladder cancer (BC), and other malignancies while the ETS family transcription factors GABPA and its partner GABPB1 activate the mutant TERT promoter and telomerase in these tumors. GABPA depletion or the disruption of the GABPA/GABPB1 complex by knocking down GABPB1 was shown to inhibit telomerase, thereby eliminating the tumorigenic potential of glioblastoma cells. GABPA/B1 is thus suggested as a cancer therapeutic target. However, it is unclear about its role in BC. Here we unexpectedly observed that GABPA ablation inhibited TERT expression, but robustly increased proliferation, stem, and invasive phenotypes and cisplatin resistance in BC cells, while its overexpression exhibited opposite effects, and inhibited in vivo metastasizing in a xenograft transplant model. Mechanistically, GABPA directly activates the transcription of FoxA1 and GATA3, key transcription factors driving luminal differentiation of urothelial cells. Consistently, TCGA/GEO dataset analyses show that GABPA expression is correlated positively with luminal while negatively with basal signatures. Luminal tumors express higher GABPA than do basal ones. Lower GABPA expression is associated with the GABPA gene methylation or deletion (especially in basal subtype of BC tumors), and predicted significantly shorter patient survival based on TCGA and our cohort of BC patient analyses. Taken together, GABPA dictates luminal identity of BC cells and inhibits aggressive diseases in BC by promoting cellular differentiation despite its stimulatory effect on telomerase/TERT activation. Given these biological functions and its frequent methylation and/or deletion, GABPA serves as a tumor suppressor rather than oncogenic factor in BC. The GABPA effect on oncogenesis is context-dependent and its targeting for telomerase inhibition in BC may promote disease metastasizing.

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Section: Discussionsupporting

confidence: 66%

GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer

Guo

Yuan

et al. 2019

Cell Death Differ

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“…However, a key challenge is how to translate these findings into a telomerase-based therapeutic strategy. The ETS family member GABPB1, required for the TERT transcription in TERT promoter-bearing glioblastoma cells, has been proposed as a target for glioblastoma treatment [56], but our results showed that inhibiting GABPA or GABPB1 robustly increased invasiveness of TC cells despite significant downregulation of TERT expression [59]. Likely, the GABPA/B function is context-dependent.…”

Section: Discussionmentioning

confidence: 57%

“…Surprisingly, however, our results obtained from thyroid cancer (TC) studies question it as a therapeutic target [59]. First, GABPA depletion leads to significant downregulation of TERT expression in TC-derived cells independently of TERT promoter mutations; Second, GABPA expression is negatively correlated with TERT expression in primary tumors from TC patients; Third, GABPA depletion robustly increases thyroid cancer cell invasion despite a diminished TERT expression.…”

Section: The Tert Gene and Its Promoter And Transcriptsmentioning

confidence: 86%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

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“…Intriguingly, it was recently reported that GABPA controls the cell cycle and induces cell differentiation, thus acting as a tumor suppressor regulating cell proliferation, stemness, and adhesion. It decreased tumor invasiveness and distal metastases in PTC, HCC, and bladder carcinoma [154][155][156]. GABPA levels were decreased and even negatively associated with TERT expression in PTC [154][155][156].…”

Section: Discussionmentioning

confidence: 93%

“…It decreased tumor invasiveness and distal metastases in PTC, HCC, and bladder carcinoma [154][155][156]. GABPA levels were decreased and even negatively associated with TERT expression in PTC [154][155][156]. One possible explanation is that other Ets/TCF family transcription factors bind TERTp mutations.…”

Section: Discussionmentioning

confidence: 99%

The Solo Play of TERT Promoter Mutations

Hafezi

Perez-Bercoff

2020

Cells

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The reactivation of telomerase reverse transcriptase (TERT) protein is the principal mechanism of telomere maintenance in cancer cells. Mutations in the TERT promoter (TERTp) are a common mechanism of TERT reactivation in many solid cancers, particularly those originating from slow-replicating tissues. They are associated with increased TERT levels, telomere stabilization, and cell immortalization and proliferation. Much effort has been invested in recent years in characterizing their prevalence in different cancers and their potential as biomarkers for tumor stratification, as well as assessing their molecular mechanism of action, but much remains to be understood. Notably, they appear late in cell transformation and are mutually exclusive with each other as well as with other telomere maintenance mechanisms, indicative of overlapping selective advantages and of a strict regulation of TERT expression levels. In this review, we summarized the latest literature on the role and prevalence of TERTp mutations across different cancer types, highlighting their biased distribution. We then discussed the need to maintain TERT levels at sufficient levels to immortalize cells and promote proliferation while remaining within cell sustainability levels. A better understanding of TERT regulation is crucial when considering its use as a possible target in antitumor strategies.Cells 2020, 9, 749 2 of 28 by copy number variants (CNV), TERT or TERTp structural variants, chromosomal rearrangements juxtaposing TERTp to enhancer elements, cellular and viral oncogenes such as Hepatitis B virus (HBV) X protein (HBx) or high-risk Human papillomavirus (HPV)16 and HPV18 E6 oncoprotein, and, last but not least, mutations within TERTp (31% of TERT-expressing cancers) ( Figure 1A) [10, 30-38] (reviewed in [3,4,9,18-20,39]). Increased TERTp methylation is typically recorded in >50% of TERT-expressing tumors and cell lines [10,[40][41][42][43][44][45][46][47]. Epigenetic regulation of TERTp is based on altered methylation patterns of specific regions. Hypomethylation of the region between −200 and −100 from the Translational Start site (TSS), encompassing the core promoter, enables binding of c-Myc and Sp-1, thus reactivating transcription. In contrast, the region spanning exon 1 (positions +1 to ±100 from the TSS) contains a binding site for the DNA insulator CTCF. Hypermethylation of this region disrupts binding of CTCF and therefore allows TERT transcription [41][42][43][44]. Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44].

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GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression

Cited by 44 publications

References 47 publications

GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer

GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

The Solo Play of TERT Promoter Mutations

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