Dataset Information

Targeting the DNA Damage Response in OSCC with TP53 Mutations.

ABSTRACT: Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the current treatments for OSCC patients. Despite recent advances in these treatment modalities, the overall survival remains poor over the past years. Recent data from whole-exome sequencing reveal that TP53 is commonly mutated in human papillomavirus-negative OSCC patients. Furthermore, these data stressed the importance of the TP53 gene in suppressing the development and progression of OSCC. Clinically, TP53 mutations are largely associated with poor survival and tumor resistance to radiotherapy and chemotherapy in OSCC patients, which makes the TP53 mutation status a potentially useful molecular marker prognostic and predictive of clinical response in these patients. Several forms of DNA damage have been shown to activate p53, including those generated by ionizing radiation and chemotherapy. The DNA damage stabilizes p53 in part via the DNA damage signaling pathway that involves sensor kinases, including ATM and ATR and effector kinases, such as Chk1/2 and Wee1, which leads to posttranscriptional regulation of a variety of genes involved in DNA repair, cell cycle control, apoptosis, and senescence. Here, we discuss the link of TP53 mutations with treatment outcome and survival in OSCC patients. We also provide evidence that small-molecule inhibitors of critical proteins that regulate DNA damage repair and replication stress during the cell cycle progression, as well as other molecules that restore wild-type p53 activity to mutant p53, can be exploited as novel therapeutic approaches for the treatment of OSCC patients bearing p53 mutant tumors.

SUBMITTER: Lindemann A

PROVIDER: S-EPMC5960880 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Targeting the DNA Damage Response in OSCC with TP53 Mutations.

Lindemann A A Takahashi H H Patel A A AA Osman A A AA Myers J N JN

Journal of dental research 20180228 6

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer worldwide and in the United States. OSCC remains a major cause of morbidity and mortality in patients with head and neck cancers. Tobacco and alcohol consumption alone or with chewing betel nut are potential risk factors contributing to the high prevalence of OSCC. Multimodality therapies, including surgery, chemotherapy, biologic therapy, and radiotherapy, particularly intensity-modulated radiotherapy (IMRT), are the cur ...[more]

PMID: 29489434

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Project description:RATIONALE:Mutations in the LMNA gene, encoding LMNA (lamin A/C), are responsible for laminopathies. Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in laminopathies. OBJECTIVE:To gain insights into the molecular pathogenesis of DCM in laminopathies. METHODS AND RESULTS:We generated a tet-off bigenic mice expressing either a WT (wild type) or a mutant LMNA (D300N) protein in cardiac myocytes. LMNAD300N mutation is associated with DCM in progeroid syndromes. Expression of LMNAD300N led to severe myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. Administration of doxycycline suppressed LMNAD300N expression and prevented the phenotype. Whole-heart RNA sequencing in 2-week-old WT and LMNAD300N mice led to identification of ≈6000 differentially expressed genes. Gene Set Enrichment and Hallmark Pathway analyses predicted activation of E2F (E2F transcription factor), DNA damage response, TP53 (tumor protein 53), NFκB (nuclear factor κB), and TGFβ (transforming growth factor-β) pathways, which were validated by Western blotting, quantitative polymerase chain reaction of selected targets, and immunofluorescence staining. Differentially expressed genes involved cell death, cell cycle regulation, inflammation, and epithelial-mesenchymal differentiation. RNA sequencing of human hearts with DCM associated with defined LMNA pathogenic variants corroborated activation of the DNA damage response/TP53 pathway in the heart. Increased expression of CDKN2A (cyclin-dependent kinase inhibitor 2A)-a downstream target of E2F pathway and an activator of TP53-provided a plausible mechanism for activation of the TP53 pathway. To determine pathogenic role of TP53 pathway in DCM, Tp53 gene was conditionally deleted in cardiac myocytes in mice expressing the LMNAD300N protein. Deletion of Tp53 partially rescued myocardial fibrosis, apoptosis, proliferation of nonmyocyte cells, left ventricular dilatation and dysfunction, and slightly improved survival. CONCLUSIONS:Cardiac myocyte-specific expression of LMNAD300N, associated with DCM, led to pathogenic activation of the E2F/DNA damage response/TP53 pathway in the heart and induction of myocardial fibrosis, apoptosis, cardiac dysfunction, and premature death. The findings denote the E2F/DNA damage response/TP53 axis as a responsible mechanism for DCM in laminopathies and as a potential intervention target.

Project description:Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia-telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation.

Dataset Information

Targeting the DNA Damage Response in OSCC with TP53 Mutations.

Publications

Targeting the DNA Damage Response in OSCC with TP53 Mutations.

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