The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

Napoli, Marco; Flores, Elsa R.

doi:10.1080/15476286.2019.1710054

Cited by 5 publications

(5 citation statements)

References 181 publications

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“…LncRNAs constitute an ever-growing category of functional RNA species known to impinge on all hallmarks of cancer 33,52,53 . Here, we report the identification of two TAp63-regulated oncogenic lncRNAs or TROLLs, by using both genetically engineered and xenograft mouse models as well as a pan-cancer approach, including the analysis of 723 clinical cases and TCGA overall survival datasets.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Napoli

Ackerman

et al. 2020

Nat Commun

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The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Napoli

Ackerman

et al. 2020

Nat Commun

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“…The net result is decreased ubiquitination of p53, and thus increased level of p53 protein (Figure 7C ). Regulation of tumor suppressor p53 is essential for maintenance of genome integrity ( 72 , 73 ), innate immune response ( 74 ), stem cells and development ( 75 ). Interestingly, as a feedback regulation, MDM2 and members of TRIM family are high-confidence p53 target genes ( 76 ).…”

Section: Discussionmentioning

confidence: 99%

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

et al. 2020

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Interactions of KRAB (Krüppel-associated box)-associated protein KAP1 [also known as TRIM28 (tripartite motif containing protein 28)] with DNA-binding KRAB zinc finger (KRAB-ZF) proteins silence many transposable elements during embryogenesis. However, in some cancers, TRIM28 is upregulated and interacts with different partners, many of which are transcription regulators such as EZH2 in MCF7 cells, to form abnormal repressive or activating complexes that lead to misregulation of genes. We ask whether a KRAB domain—the TRIM28 interaction domain present in native binding partners of TRIM28 that mediate repression of transposable elements—could be used as a tool molecule to disrupt aberrant TRIM28 complexes. Expression of KRAB domain containing fragments from a KRAB-ZF protein (ZFP568) in MCF7 cells, without the DNA-binding zinc fingers, inhibited TRIM28–EZH2 interactions and caused degradation of both TRIM28 and EZH2 proteins as well as other components of the EZH2-associated polycomb repressor 2 complex. In consequence, the product of EZH2 enzymatic activity, trimethylation of histone H3 lysine 27 level, was significantly reduced. The expression of a synthetic KRAB domain significantly inhibits the growth of breast cancer cells (MCF7) but has no effect on normal (immortalized) human mammary epithelial cells (MCF10a). Further, we found that TRIM28 is a positive regulator of TRIM24 protein levels, as observed previously in prostate cancer cells, and expression of the KRAB domain also lowered TRIM24 protein. Importantly, reduction of TRIM24 levels, by treatment with either the KRAB domain or a small-molecule degrader targeted to TRIM24, is accompanied by an elevated level of tumor suppressor p53. Taken together, this study reveals a novel mechanism for a TRIM28-associated protein stability network and establishes TRIM28 as a potential therapeutic target in cancers where TRIM28 is elevated. Finally, we discuss a potential mechanism of KRAB-ZF gene expression controlled by a regulatory feedback loop of TRIM28–KRAB.

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“…To date, the biomarkers are commonly used in early screening for all kinds of cancers ( Yuan et al, 2020 ), and lncRNAs have attracted increasing attention as cancer biomarkers for early screening, diagnosis, prognosis, and responses to drug treatment ( Zhang et al, 2018 ; Necula et al, 2019 ; Zhuo et al, 2019 ). LncRNAs constitute an ever-growing category of functional RNA species known to impinge on all hallmarks of cancer ( Napoli and Flores, 2020 ). Many studies revealed that lncRNAs could regulate many important pathological processes in cancer, such as tumorigenesis, tumor progression, proliferation, metastasis, and drug resistance ( Fang and Fullwood, 2016 ; Schmitt and Chang, 2016 ), suggesting an enormous potential for further development of lncRNA biomarkers in specific cancer histologic analysis.…”

Section: Long Non-coding Rnas Serve As a Promising Target In The Trea...mentioning

confidence: 99%

Long non-coding RNAs play an important regulatory role in tumorigenesis and tumor progression through aerobic glycolysis

Fan

Feng

et al. 2022

Front. Mol. Biosci.

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Compared to normal cells, cancer cells generate ATP mainly through aerobic glycolysis, which promotes tumorigenesis and tumor progression. Long non-coding RNAs (LncRNAs) are a class of transcripts longer than 200 nucleotides with little or without evident protein-encoding function. LncRNAs are involved in the ten hallmarks of cancer, interestingly, they are also closely associated with aerobic glycolysis. However, the mechanism of this process is non-transparent to date. Demonstrating the mechanism of lncRNAs regulating tumorigenesis and tumor progression through aerobic glycolysis is particularly critical for cancer therapy, and may provide novel therapeutic targets or strategies in cancer treatment. In this review, we discuss the role of lncRNAs and aerobic glycolysis in tumorigenesis and tumor progression, and further explore their interaction, in hope to provide a novel therapeutic target for cancer treatment.

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The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

Cited by 5 publications

References 181 publications

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation

KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells

Long non-coding RNAs play an important regulatory role in tumorigenesis and tumor progression through aerobic glycolysis

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