MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response

Qiu, Huan; Jin, Bangming; Wang, Zhanfeng; Zheng, Qi-Fan; Zhang, Li; Zhu, Ling-Yu; Shi, Shuang; Yuan, Jun-Bo; Lin, Xiao; Gao, Shu-Bin; Jin, Guang‐Hui

doi:10.1038/s41467-020-14614-4

Cited by 30 publications

(40 citation statements)

References 36 publications

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“…In addition, several bromodomain proteins identified as putative STING partners here (e.g., BRD2, BRD3) could also explain this chromatin compaction function or, more excitingly, chromatin remodeling reported to occur in IIRs (Mehta and Jeffrey, 2015). Furthermore, MEN1 is a tumor suppressor (Fang et al, 2013) and as such could contribute to reported STING roles in DNA damage sensing in cancer (Ablasser and Chen, 2019;Gentili et al, 2019;Mackenzie et al, 2017;Ng et al, 2018;Qiu et al, 2020;Zierhut et al, 2019). A recent study showed that MEN1 depletion results in misregulation of the p53 pathway leading to increased levels of chromosomal instability and accumulation of DNA damage (Qiu et al, 2020).…”

Section: Discussionmentioning

confidence: 72%

STING nuclear partners contribute to innate immune signaling responses

et al. 2021

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STimulator of INterferon Genes (STING) is an adaptor for cytoplasmic DNA sensing by cGAMP/cGAS that helps trigger innate immune responses (IIRs). Although STING is mostly localized in the ER, we find a separate inner nuclear membrane pool of STING that increases mobility and redistributes to the outer nuclear membrane upon IIR stimulation by transfected dsDNA or dsRNA mimic poly(I:C). Immunoprecipitation of STING from isolated nuclear envelopes coupled with mass spectrometry revealed a distinct nuclear envelope-STING proteome consisting of known nuclear membrane proteins and enriched in DNA-and RNA-binding proteins. Seventeen of these nuclear envelope STING partners are known to bind direct interactors of IRF3/7 transcription factors, and testing a subset of these revealed STING partners SYNCRIP, MEN1, DDX5, snRNP70, RPS27a, and AATF as novel modulators of dsDNA-triggered IIRs. Moreover, we find that SYNCRIP is a novel antagonist of the RNA virus, influenza A, potentially shedding light on reports of STING inhibition of RNA viruses.

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Section: Discussionmentioning

confidence: 72%

STING nuclear partners contribute to innate immune signaling responses

et al. 2021

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“…The MEN1 splice site 927 + 1G>A has been described on germline allele and considered as likely pathogenic (ClinVar). This loss of menin, an epigenetic regulator, leads to the inactivation of p53/Rb pathways and triggers aberrant DNA damage response ( 19 ). DAXX mutations, observed in 20% of pancreatic NETs, are usually correlated with a poor prognosis; they can be driver mutations ( 5 ) and play a role in chromosomal instability ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components

et al. 2021

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Temporal and spatial tumor heterogeneity can be observed in pancreatic neuroendocrine tumor. We report the case of a young woman with long term stabilization of a G2 metastatic pancreatic NET that, after pregnancy, suddenly progressed into one single liver metastasis corresponding to a transformation into G3 large-cell neuroendocrine cancer. The patient underwent liver resection (the progressive and one dormant metastasis). With a 45 months follow-up the patient is without evolutive disease. Exome sequencing of the two metastases revealed completely different genomic signatures and gene alterations: the dormant metastasis was MSS without any gene alteration; the poorly differentiated tumor was MSI, with gain of many mutations including MEN1, BCL2, MLH1 and TP53 corresponding to a mutational signature 11. Could temozolomide play a role in this transformation?

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“…4 and 5). In addition, menin and EBV proteins may have opposite actions on tumor protein 53 (p53) and retinoblastoma (Rb) activity, (32,33) as expected of tumor suppressors and oncogenes, respectively, and investigations of the possible roles of these pathways and their components in controlling menin expression, may help to advance knowledge of the mechanisms regulating MEN1 transcription and translation.…”

Section: Discussionmentioning

confidence: 99%

Multiple Endocrine Neoplasia Type 1 (MEN1) 5′UTR Deletion, in MEN1 Family, Decreases Menin Expression

Kooblall

Boon

Cranston

et al. 2020

Journal of Bone and Mineral Research

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of parathyroid, pancreatic and pituitary tumors, and is due to mutations in the coding region of the MEN1 gene, which encodes menin. We investigated a family with identical twins that had MEN1, with different MEN1 tumors. DNA sequence analysis of the MEN1 coding region had not identified any abnormalities and we hypothesized that deletions and mutations involving the untranslated regions may be involved. Informed consent and venous blood samples were obtained from five family members. Sanger DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) analyses were performed using leukocyte DNA. This revealed a heterozygous 596bp deletion (Δ596bp) between nucleotides −1087 and −492 upstream of the translation start site, located within the MEN1 5 0 untranslated region (UTR), and includes the core promoter and multiple cis-regulatory regions. To investigate the effects of this 5 0 UTR deletion on MEN1 promoter activity, we generated luciferase reporter constructs, containing either wild-type 842bp or mutant 246bp MEN1 promoter, and transfected them into human embryonic kidney HEK293 and pancreatic neuroendocrine tumor BON-1 cells. This revealed the Δ596bp mutation to result in significant reductions by 37-fold (p < 0.0001) and 16-fold (p < 0.0001) in luciferase expression in HEK293 and BON-1 cells, respectively, compared to wild-type. The effects of this 5 0 UTR deletion on MEN1 transcription and translation were assessed using qRT-PCR and Western blot analyses, respectively, of mRNA and protein lysates obtained from Epstein-Barr-virus transformed lymphoblastoid cells derived from affected and unaffected individuals. This demonstrated the Δ596bp mutation to result in significant reductions of 84% (p < 0.05) and 88% (p < 0.05) in MEN1 mRNA and menin protein, respectively, compared to unaffected individuals. Thus, our results report the first germline MEN1 5 0 UTR mutation and highlight the importance of investigating UTRs in MEN1 patients who do not have coding region mutations.

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MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response

Cited by 30 publications

References 36 publications

STING nuclear partners contribute to innate immune signaling responses

STING nuclear partners contribute to innate immune signaling responses

Case Report: Grade 2 Metastatic Pancreatic Neuroendocrine Tumor With Progression of One Metastasis After Pregnancy to Grade 3 Large-Cell Neuroendocrine Carcinoma: One Case Cured by Resection With Genomic Characterization of the Two Components

Multiple Endocrine Neoplasia Type 1 (MEN1) 5′UTR Deletion, in MEN1 Family, Decreases Menin Expression

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