Roles of p53 and pRB Tumor Suppressor Networks in Human Cancer: Insight from Studies in the Engineered Mouse

Background/AimsThe role of DHRS3 in human cancer remains unclear. Our study explored the role of DHRS3 in gastric cancer (GC) and its clinicopathological significance and associated mechanisms.MaterialsBisulfite-assisted genomic sequencing PCR and a Mass-Array system were used to evaluate and quantify the methylation levels of the promoter. The expression levels and biological function of DHRS3 was examined by both in vitro and in vivo assays. A two-way hierarchical cluster analysis was used to classify the methylation profiles, and the correlation between the methylation status of the DHRS3 promoter and the clinicopathological characteristics of GC were then assessed.ResultsThe DHRS3 promoter was hypermethylated in GC samples, while the mRNA and protein levels of DHRS3 were significantly downregulated. Ectopic expression of DHRS3 in GC cells inhibited cell proliferation and migration in vitro, decreased tumor growth in vivo. DHRS3 methylation was correlated with histological type and poor differentiation of tumors. GC patients with high degrees of CpG 9.10 methylation had shorter survival times than those with lower methylation.ConclusionDHRS3 was hypermethylated and downregulated in GC patients. Reduced expression of DHRS3 is implicated in gastric carcinogenesis, which suggests DHRS3 is a tumor suppressor.

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The Impact of Mutant p53 in the Non-Coding RNA World

Biomolecules ◽

10.3390/biom10030472 ◽

2020 ◽

Vol 10 (3) ◽

pp. 472

Author(s):

Silvia Di Agostino

Keyword(s):

Tumor Suppressor ◽

Human Cancer ◽

Rna World ◽

Circular Rnas ◽

Mutant P53 ◽

Suppressor Activity ◽

Protein Coding ◽

Micro Rnas ◽

Non Coding Rnas ◽

The Impact

Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.

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CHK2–BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1525129113 ◽

2016 ◽

Vol 113 (7) ◽

pp. 1817-1822 ◽

Cited By ~ 26

Author(s):

Norman Ertych ◽

Ailine Stolz ◽

Oliver Valerius ◽

Gerhard H. Braus ◽

Holger Bastians

Keyword(s):

Tumor Suppressor ◽

Human Cancer ◽

Microtubule Assembly ◽

Cancer Type ◽

Aurora A Kinase ◽

Aurora A ◽

Mitotic Spindles ◽

Human Cancer Cells ◽

Chromosome Missegregation ◽

Open Question

BRCA1 (breast cancer type 1 susceptibility protein) is a multifunctional tumor suppressor involved in DNA damage response, DNA repair, chromatin regulation, and mitotic chromosome segregation. Although the nuclear functions of BRCA1 have been investigated in detail, its role during mitosis is little understood. It is clear, however, that loss of BRCA1 in human cancer cells leads to chromosomal instability (CIN), which is defined as a perpetual gain or loss of whole chromosomes during mitosis. Moreover, our recent work has revealed that the mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase Chk2 (checkpoint kinase 2) and that this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles. Intriguingly, loss of the positive regulation of BRCA1 leads to increased oncogenic Aurora-A activity, which acts as a mediator for abnormal mitotic microtubule assembly resulting in chromosome missegregation and CIN. However, how the CHK2–BRCA1 tumor suppressor axis restrains oncogenic Aurora-A during mitosis to ensure karyotype stability remained an open question. Here we uncover a dual molecular mechanism by which the CHK2–BRCA1 axis restrains oncogenic Aurora-A activity during mitosis and identify BRCA1 itself as a target for Aurora-A relevant for CIN. In fact, Chk2-mediated phosphorylation of BRCA1 is required to recruit the PP6C–SAPS3 phosphatase, which acts as a T-loop phosphatase inhibiting Aurora-A bound to BRCA1. Consequently, loss of CHK2 or PP6C-SAPS3 promotes Aurora-A activity associated with BRCA1 in mitosis. Aurora-A, in turn, then phosphorylates BRCA1 itself, thereby inhibiting the mitotic function of BRCA1 and promoting mitotic microtubule assembly, chromosome missegregation, and CIN.

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Role of the p16 tumor suppressor gene in cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.3.1197 ◽

1998 ◽

Vol 16 (3) ◽

pp. 1197-1206 ◽

Cited By ~ 399

Author(s):

W H Liggett ◽

D Sidransky

Keyword(s):

Cell Cycle ◽

Tumor Suppressor ◽

Tumor Suppressor Gene ◽

Human Cancer ◽

Suppressor Gene ◽

Premalignant Lesions ◽

Early Event ◽

Cyclin Dependent Kinase ◽

Primary Tumors

Since its discovery as a CDKI (cyclin-dependent kinase inhibitor) in 1993, the tumor suppressor p16 (INK4A/MTS-1/CDKN2A) has gained widespread importance in cancer. The frequent mutations and deletions of p16 in human cancer cell lines first suggested an important role for p16 in carcinogenesis. This genetic evidence for a causal role was significantly strengthened by the observation that p16 was frequently inactivated in familial melanoma kindreds. Since then, a high frequency of p16 gene alterations were observed in many primary tumors. In human neoplasms, p16 is silenced in at least three ways: homozygous deletion, methylation of the promoter, and point mutation. The first two mechanisms comprise the majority of inactivation events in most primary tumors. Additionally, the loss of p16 may be an early event in cancer progression, because deletion of at least one copy is quite high in some premalignant lesions. p16 is a major target in carcinogenesis, rivaled in frequency only by the p53 tumor-suppressor gene. Its mechanism of action as a CDKI has been elegantly elucidated and involves binding to and inactivating the cyclin D-cyclin-dependent kinase 4 (or 6) complex, and thus renders the retinoblastoma protein inactive. This effect blocks the transcription of important cell-cycle regulatory proteins and results in cell-cycle arrest. Although p16 may be involved in cell senescence, the physiologic role of p16 is still unclear. Future work will focus on studies of the upstream events that lead to p16 expression and its mechanism of regulation, and perhaps lead to better therapeutic strategies that can improve the clinical course of many lethal cancers.

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A High-Throughput Screen with Isogenic PTEN+/+ and PTEN−/− Cells Identifies CID1340132 as a Novel Compound That Induces Apoptosis in PTEN and PIK3CA Mutant Human Cancer Cells

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057110397357 ◽

2011 ◽

Vol 16 (4) ◽

pp. 383-393 ◽

Cited By ~ 7

Author(s):

Hui-Fang Li ◽

Adam Keeton ◽

Michele Vitolo ◽

Clinton Maddox ◽

Lynn Rasmussen ◽

...

Keyword(s):

Tumor Suppressor ◽

Cancer Cells ◽

Tumor Suppressor Gene ◽

High Throughput ◽

Human Cancer ◽

Genetic Difference ◽

Suppressor Gene ◽

Pten Gene ◽

Target Cells ◽

Mutant Cells

The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N′-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. Taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells.

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Down-regulation of the Tumor Suppressor C-terminal Src Kinase (Csk)-binding Protein (Cbp)/PAG1 Is Mediated by Epigenetic Histone Modifications via the Mitogen-activated Protein Kinase (MAPK)/Phosphatidylinositol 3-Kinase (PI3K) Pathway

Journal of Biological Chemistry ◽

10.1074/jbc.m110.195362 ◽

2011 ◽

Vol 286 (18) ◽

pp. 15698-15706 ◽

Cited By ~ 25

Author(s):

Kei Suzuki ◽

Chitose Oneyama ◽

Hironobu Kimura ◽

Shoji Tajima ◽

Masato Okada

Keyword(s):

Tumor Suppressor ◽

Cancer Cells ◽

Histone Modifications ◽

Human Cancer ◽

Methylation Status ◽

Adaptor Protein ◽

Pi3k Pathway ◽

Mitogen Activated Protein Kinase ◽

Down Regulation ◽

Human Cancer Cells

The transmembrane adaptor protein Cbp (or PAG1) functions as a suppressor of Src-mediated tumor progression by promoting the inactivation of Src. The expression of Cbp is down-regulated in Src-transformed cells and in various human cancer cells, suggesting a potential role for Cbp as a tumor suppressor. However, the mechanisms underlying the down-regulation of Cbp remain unknown. The present study shows that Cbp expression is down-regulated by epigenetic histone modifications via the MAPK/PI3K pathway. In mouse embryonic fibroblasts, transformation by oncogenic Src and Ras induced a marked down-regulation of Cbp expression. The levels of Cbp expression were inversely correlated with the activity of MEK and Akt, and Cbp down-regulation was suppressed by inhibiting MEK and PI3K. Src transformation did not affect the stability of Cbp mRNA, the transcriptional activity of the cbp promoter, or the DNA methylation status of the cbp promoter CpG islands. However, Cbp expression was restored by treatment with histone deacetylase (HDAC) inhibitors and by siRNA-mediated knockdown of HDAC1/2. Src transformation significantly decreased the acetylation levels of histone H4 and increased the trimethylation levels of histone H3 lysine 27 in the cbp promoter. EGF-induced Cbp down-regulation was also suppressed by inhibiting MEK and HDAC. Furthermore, the inhibition of MEK or HDAC restored Cbp expression in human cancer cells harboring Cbp down-regulation through promoter hypomethylation. These findings suggest that Cbp down-regulation is primarily mediated by epigenetic histone modifications via oncogenic MAPK/PI3K pathways in a subset of cancer cells.

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