A cancer‐associated <i>CDKN1B</i> mutation induces p27 phosphorylation on a novel residue: a new mechanism for tumor suppressor loss‐of‐function

Bencivenga, Debora; Stampone, Emanuela; Aulitto, Arianna; Tramontano, Annunziata; Barone, Clementina; Negri, Aide; Roberti, Domenico; Perrotta, Silverio; Ragione, Fulvio Della; Borriello, Adriana

doi:10.1002/1878-0261.12881

Cited by 14 publications

(8 citation statements)

References 64 publications

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“…In our literature search, we found consistent previous reports regarding 21 of these 45 genes (Additional file 1 : Table S15). Among the genes adjacent to these promoters, CDKN1B, ZFP82, SHISA3, GPX7, and IRF8 are known TSGs [ 21 – 25 ]. The hypermethylation of KCNA3 , IRF8, and ZNF529 was also reported by Foy et al [ 26 ] in leukoplakia transforming into OSCC, implying important early events which might play a role in disease progression.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers

et al. 2023

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Background Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis. Results There is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls. Conclusions Our findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers

et al. 2023

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“…The mRNA expression level of TWIST1 and p27 was measured using the primers as previously reported [ 26 , 27 , 73 ]. Briefly, total RNA was isolated using QIAprep RNeasy Kit (Qiagen) as per manufacturer’s instruction followed by reverse transcription into cDNA (Applied Biosystems kit).…”

Section: Methodsmentioning

confidence: 99%

TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer

Kumar,

Yochum,

Devadassan

et al. 2024

Oncogene

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MET amplification/mutations are important targetable oncogenic drivers in NSCLC, however, acquired resistance is inevitable and the majority of patients with targetable MET alterations fail to respond to MET tyrosine kinase inhibitors (TKIs). Furthermore, MET amplification is among the most common mediators of TKI resistance. As such, novel therapies to target MET pathway and overcome MET TKI resistance are clearly needed. Here we show that the epithelial-mesenchymal transition (EMT) transcription factor, TWIST1 is a key downstream mediator of HGF/MET induced resistance through suppression of p27 and targeting TWIST1 can overcome resistance. We found that TWIST1 is overexpressed at the time of TKI resistance in multiple MET-dependent TKI acquired resistance PDX models. We have shown for the first time that MET directly stabilized the TWIST protein leading to TKI resistance and that TWIST1 was required for MET-driven lung tumorigenesis as well as could induce MET TKI resistance when overexpressed. TWIST1 mediated MET TKI resistance through suppression of p27 expression and genetic or pharmacologic inhibition of TWIST1 overcame TKI resistance in vitro and in vivo. Our findings suggest that targeting TWIST1 may be an effective therapeutic strategy to overcome resistance in MET-driven NSCLC as well as in other oncogene driven subtypes in which MET amplification is the resistance mechanism.

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“…Immunofluorescence microscopy was performed as in Bencivenga et al, 2021 [ 41 ]. Cells were grown in 8-well tissue culture chambers (Ibidi, Gräfelfing-Bayern, Germany) and transfected for 24 h with the plasmids indicated before.…”

Section: Methodsmentioning

confidence: 99%

A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57Kip2

Stampone

Bencivenga

Barone

et al. 2021

IJMS

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p57Kip2 protein is a member of the CIP/Kip family, mainly localized in the nucleus where it exerts its Cyclin/CDKs inhibitory function. In addition, the protein plays key roles in embryogenesis, differentiation, and carcinogenesis depending on its cellular localization and interactors. Mutations of CDKN1C, the gene encoding human p57Kip2, result in the development of different genetic diseases, including Beckwith–Wiedemann, IMAGe and Silver–Russell syndromes. We investigated a specific Beckwith–Wiedemann associated CDKN1C change (c.946 C>T) that results in the substitution of the C-terminal amino acid (arginine 316) with a tryptophan (R316W-p57Kip2). We found a clear redistribution of R316W-p57Kip2, in that while the wild-type p57Kip2 mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57Kip2 N- and C-terminal domain, respectively, allows the mapping of the nuclear localization signal(s) (NLSs) between residues 220–316. Moreover, by removing the basic RKRLR sequence at the protein C-terminus (from 312 to 316 residue), p57Kip2 was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57Kip2 NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57Kip2 localization/regulatory roles.

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A cancer‐associated CDKN1B mutation induces p27 phosphorylation on a novel residue: a new mechanism for tumor suppressor loss‐of‐function

Cited by 14 publications

References 64 publications

Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers

Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers

TWIST1 is a critical downstream target of the HGF/MET pathway and is required for MET driven acquired resistance in oncogene driven lung cancer

A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57Kip2

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