PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation

Hou, Shengqi; Ouyang, Meng; Brandmaier, Andrew; Hao, Hongbo; Shen, Wen Hong

doi:10.1002/bies.201700082

Cited by 60 publications

(51 citation statements)

References 49 publications

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“…The DLG2 GSEA of the NB datasets showed enrichment for Falconi anemia pathway, this is a DNA repair pathway (Tables 1 and 2), the functional loss of which is known result in an increased number of chromosomal breaks. DNA integrity is also one of the key functions of the G2/M checkpoint (32) and is lost if cells rapidly or abruptly leave the S phase. We have shown that DLG2 can regulate the cell cycle, namely by slowing the progression of cells through the G2/M checkpoint (Fig.…”

Section: Discussionmentioning

confidence: 99%

Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival.

Keane

Améen

Lindlöf

et al. 2020

Preprint

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Neuroblastoma (NB) is a childhood neural crest tumor. There are two groups of aggressive NBs, one with MYCN amplification, and another with 11q chromosomal deletion; these chromosomal aberrations are generally mutually exclusive. The DLG2 gene resides in the 11q-deleted region, thus makes it an interesting NB candidate tumor suppressor gene. Methods We evaluated the association of DLG2 gene expression in NB with patient outcomes, stage and MYCN status, using online microarray data combining independent NB patient data sets. Functional studies were also conducted using NB cell models and the fruit fly. Results Using the array data we concluded that higher DLG2 expression was positively correlated to patient survival. We could also see that expression of DLG2 was inversely correlated with MYCN status and tumor stage. Cell proliferation was lowered in both 11q-normal and 11q-deleted NB cells after DLG2 over expression, and increased in 11q-normal NB cells after DLG2 silencing. Higher level of DLG2 increased the percentage of cells in the G2/M phase and decreased the percentage of cells in the G1 phase. We detected increased protein levels of Cyclin A and Cyclin B in a fruit fly model over expressing dMyc or silencing dmDLG , indicating that both events results in enhanced cell cycling. Induced MYCN expression in NB cells, lowered DLG2 gene expression, this was confirmed in the fly, when dMyc was over expressed, the dmDLG protein level was lowered, indicating a link between Myc over expression and low dmDLG level. Conclusion We conclude that low DLG2 expression level forces cell cycle progression, and that it predicts poor NB patient survival. The low DLG2 expression level could be caused by either MYCN -amplification or 11q-deletion.

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Section: Discussionmentioning

confidence: 99%

Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival.

Keane

Améen

Lindlöf

et al. 2020

Preprint

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“…More recent evidence has shown that PTEN has phosphatase-independent roles in the nucleus where it regulates DNA replication and repair, chromatin dynamics, chromosome stability, and many other biological processes (23,24). Ma et al recently demonstrated that the majority of nuclear PTEN is phosphorylated at tyrosine residue-240 (pY240-PTEN) and that this phosphorylation was essential for PTEN's ability to bind chromatin, recruit RAD51…”

Section: Nuclear Pten Contributes To Mln4924 Sensitivity Through Its mentioning

confidence: 99%

“…PTEN has been shown to be directly involved in DNA fork progression, protection, and processing, and these pathways were among the most significant that differentiated sensitive and resistant groups (23,24). We aimed to test whether enrichment in replication fork processing and protection associated gene sets could predict MLN4924 response.…”

Section: Low Enrichment In Dna Fork Replication Pathways Can Predict mentioning

confidence: 99%

Dynamic multi-OMICs of glioblastoma reveal sensitivity to neddylation inhibition dependent on nuclear PTEN and DNA replication pathways: Nuclear PTEN mediates MLN4924 sensitivity in GBM

Ferdosi

Taylor

Lee

et al. 2020

Preprint

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Finding and matching drugs to treat subsets of cancers remains a daunting challenge of precision medicine. Neddylation inhibition, affecting posttranslational protein function and turnover, is a promising therapeutic approach to cancer including glioblastoma (GBM). We report vulnerability to neddylation inhibition by MLN4924 in a subset of GBM preclinical models and identify mechanisms underlying this differential response. MLN4924 treatment of GBM cells with intact PTEN die due to DNA damage and re-replication events. Loss of PTEN drives resistance to MLN4924. Time-course transcriptomics elevates PTEN signaling, DNA replication, and chromatin instability pathways as significant differentiators between MLN4924-sensitive and resistant models. Shotgun proteomics corroborates these findings and also identifies elevated TOP2A in resistant models. TOP2A inhibitors combined with MLN4924 prove synergistic. We show that PTEN status serves as both a novel biomarker for MLN4924 response in GBM and reveals a vulnerability to TOP2A inhibitors in combination with MLN4924.SummaryNeddylation inhibition kills glioma cells by DNA damage and re-replication events which are dependent on wild-type nuclear PTEN.

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“…PTEN loss has been extensively linked to CIN, a biological role that is largely dependent on the scaffolding rather than the phosphatase function of PTEN [81], and therefore mostly independent of PI3K/Akt activity. Given that these PTEN effects can therefore not be modulated by pharmacological intervention targeting PI3K, these will therefore not be described here.…”

Section: Ptenmentioning

confidence: 99%

“…For an excellent review on the functions of PTEN in the maintenance of genome integrity, the reader is referred to Ref. [81].…”

Section: Ptenmentioning

confidence: 99%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancercell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which -even if occurring in a low fraction of the cell population -might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

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PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation

Cited by 60 publications

References 49 publications

Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival.

Low DLG2 gene expression, a link between 11q-deleted and MYCN-amplified neuroblastoma, causes forced cell cycle progression, and predicts poor patient survival.

Dynamic multi-OMICs of glioblastoma reveal sensitivity to neddylation inhibition dependent on nuclear PTEN and DNA replication pathways: Nuclear PTEN mediates MLN4924 sensitivity in GBM

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

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