Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

Hsu, Alice H.; Lum, Michelle A.; Shim, Kang Sup; Frederick, Peter J.; Morrison, Carl; Chen, Baojiang; Lele, Subodh M.; Sheinin, Yuri; Daikoku, Takiko; Dey, Sudhansu K.; Leone, Gustavo; Black, Adrian R.; Black, Jennifer D.

doi:10.1016/j.celrep.2018.06.067

Cited by 42 publications

(48 citation statements)

References 50 publications

(77 reference statements)

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“…Cells were lysed in 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 1% Nonidet P-40, 2 mM EDTA, 0.1% SDS, 50 mM NaF, 10 mM Na3VO4, 1 mM phenylmethylsulfonyl fluoride, 25 μg/mL β-glycerophosphate, and one protease inhibitor mixture tablet from Roche, and extracts (30 μg protein) were analyzed by Western blotting as described [58]. Primary antibodies were from Cell Signaling [PARP: 95425; Caspase 7: 128275; GAPDH: 5174; HDAC1: 3565; HDAC2: 51135; HDAC3 39495; HDAC4: 7628; HDAC5: 204585; HDAC6: 76125; acetyl-α-tubulin (Lys40): 5335; acetyl-histone 3: 9649; cleaved caspase 3: 9664].…”

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Laschanzky

Humphrey

et al. 2019

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) has a five-year survival rate of <10% due in part to a lack of effective therapies. Pan-histone deacetylase (HDAC) inhibitors have shown preclinical efficacy against PDAC but have failed in the clinic due to toxicity. Selective HDAC inhibitors may reduce toxicity while retaining therapeutic efficacy. However, their use requires identification of the specific HDACs that mediate the therapeutic effects of HDAC inhibitors in PDAC. We determined that the HDAC1/2/3 inhibitor Mocetinostat synergizes with the HDAC4/5/6 inhibitor LMK-235 in a panel of PDAC cell lines. Furthermore, while neither drug alone synergizes with gemcitabine, the combination of Mocetinostat, LMK-235, and gemcitabine showed strong synergy. Using small interfering (si)RNA-mediated knockdown, this synergy was attributed to inhibition of HDACs 1, 2, and 6. Pharmacological inhibition of HDACs 1 and 2 with Romidepsin and HDAC6 with ACY-1215 also potently synergized with gemcitabine in a panel of PDAC cell lines, and this drug combination potentiated the antitumor effects of gemcitabine against PDAC xenografts in vivo. Collectively, our data show that inhibition of multiple HDACs is required for therapeutic effects of HDAC inhibitors and support the development of novel strategies to inhibit HDACs 1, 2, and 6 for PDAC therapy.

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Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Laschanzky

Humphrey

et al. 2019

Cancers

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“…Among down-regulated gene sets, we found genes associated with the tumor suppressors Atf2 , Pten , Pkca , P53 , and Rps14 , a negative regulator of c-Myc . Furthermore, genes associated with polycomb-repressive complex 1 (PRC1) were also down-regulated as well as mTORC1-regulated genes ( 39 , 40 , 41 , 42 , 43 , 44 ). Together, these data suggest that ALK-induced transformation and lymphomagenesis involves the induction of additional oncogenic pathways and the repression of tumor suppressive genes.…”

Section: Resultsmentioning

confidence: 99%

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis

et al. 2020

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Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T-cell–specific lymphoma model based on the human oncogenic nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK-positive tumors show a loss of associated methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis.

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“…In USC, PIK3CA mutation occurs in about 30% of cases (11,(34)(35), which is consistent with the involvement of the PI3K-Akt signaling pathway seen from our analysis. Inhibition of PI3K/AKT/mTOR signaling strongly suppresses EEC progression (36)(37)(38) and clinical trials targeting PI3K/AKT/mTOR signaling in solid tumors have shown promise (39). However, the bene ts of this against in endometrial cancers is controversial due to the complexity of pharmacological action and toxicity (40).…”

Section: Discussionmentioning

confidence: 99%

A 4-gene Signature Predicts Prognosis of Uterine Serous Carcinoma

Chen

Qin

Xiong

et al. 2020

Preprint

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Background: Uterine serous carcinoma (USC) is a rare, aggressive variant of endometrial cancer that accounts for more than 50% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. Methods: USC RNA-Seq data and corresponding patients’ clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. Results: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4‐gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. Conclusions: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.

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Crosstalk between PKCα and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium

Cited by 42 publications

References 50 publications

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Selective Inhibition of Histone Deacetylases 1/2/6 in Combination with Gemcitabine: A Promising Combination for Pancreatic Cancer Therapy

Requirement of DNMT1 to orchestrate epigenomic reprogramming for NPM-ALK–driven lymphomagenesis

A 4-gene Signature Predicts Prognosis of Uterine Serous Carcinoma

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