EP300 and SIRT1/6 Co-Regulate Lapatinib Sensitivity Via Modulating FOXO3-Acetylation and Activity in Breast Cancer

Mahmud, Zimam; Gomes, Ana; Lee, Hee Jin; Aimjongjun, Sathid; Jiramongkol, Yannasittha; Yao, Shang J.; Zona, Stefania; Alasiri, Glowi; Gong, Gyungyub; Yagüe, Ernesto; Lam, Eric

doi:10.3390/cancers11081067

Cited by 34 publications

(30 citation statements)

References 35 publications

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“…As a proof-of-concept, we identified genomic aberrations that correlated with our drug-sensitivity predictive signaling features. For instance, through the lapatinib-predictive median expression levels of p-MKK3 and p-MKK6 we identified the known lapatinib sensitivity predictive EP300 CNV (Mahmud et al, 2019) and the interesting PPM1D CNV, which encodes a serine threonine phosphatase amplified in approximately 8% of breast cancers (Lambros et al, 2010). Furthermore, the lapatinib-predictive p38·MK2 edge flux linked amplification of the breast cancer oncogene A1CF (Yan et al, 2017), and of ASAH2B to lapatinib resistance.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the Signaling Network Landscape of Breast Cancer Improves Drug Sensitivity Prediction

Tognetti

Gábor

Yang

et al. 2020

Preprint

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Although genetic and epigenetic abnormalities in breast cancer have been extensively studied, it remains difficult to identify those patients who will respond to particular therapies. This is due in part to our lack of understanding of how the variability of cellular signaling affects drug sensitivity. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data – on more than 80 million single cells from 4,000 conditions – were used to fit mechanistic signaling network models that provide unprecedented insights into the biological principles of how cancer cells process information. Our dynamic single-cell-based models more accurately predicted drug sensitivity than static bulk measurements for drugs targeting the PI3K-MTOR signaling pathway. Finally, we identified genomic features associated with drug sensitivity by using signaling phenotypes as proxies, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. This provides proof of principle that single-cell measurements and modeling could inform matching of patients with appropriate treatments in the future.One-linerSingle-cell proteomics coupled to perturbations improves accuracy of breast tumor drug sensitivity predictions and reveals mechanisms of sensitivity and resistance.HIGHLIGHTSMass cytometry study of signaling responses of 62 breast cancer cell lines and five lines from healthy tissue to EGF stimulation with or without perturbation with five kinase inhibitors.Single-cell signaling features and mechanistic signaling network models predicted drug sensitivity.Mechanistic signaling network models deepen the understanding of drug resistance and sensitivity mechanisms.We identify drug sensitivity-predictive genomic features via proxy signaling phenotypes.

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Section: Discussionmentioning

confidence: 99%

Deciphering the Signaling Network Landscape of Breast Cancer Improves Drug Sensitivity Prediction

Tognetti

Gábor

Yang

et al. 2020

Preprint

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“…When the FOXO3 is activated, it could induce transcription of target genes through binding to the conversed sequence motif GTAAA(C/T)A [ 21 ]. In breast cancer, Mahmud et al demonstrated that EP300 and SIRT1/6 co-regulates Lapatinib sensitivity through modulating FOXO3-acetylation and activity [ 22 ]. Another study found that lnRNA LINC01355 could stabilize FOXO3 protein and inhibit the progression of BC [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

MiR-940 promotes malignant progression of breast cancer by regulating FOXO3

et al. 2020

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Breast cancer (BC) is a common cancer with poor survival. This study aimed to explore the effect of miR-940 on the process of BC cells and its target gene FOXO3. The expression of miR-940 was assessed in BC tissues and cells using qRT-PCR. Furthermore, the correlation between miR-940 and prognosis of BC patients from the TCGA database was analyzed. CCK8 assays and colony formation assays were used to explore the effect of miR-940 on BC cell proliferation. The invasion abilities were detected by transwell assays. Luciferase reporter assay was performed to scrutinize the relationship between miR-940 and FOXO3. Finally, rescue experiments were performed through FOXO3 downregulation and miR-940 inhibitors by using CCK8 assays, colony formation assays and transwell assays. miR-940 was significantly upregulated in BC cells and tissues. In addition, the high level of miR-940 correlated with poor survival of BC patients (P=0.023). CCK8 assays, colony formation assays and transwell assays indicated that miR-940 promoted the proliferation and invasion abilities of BC cells. The luciferase reporter assay suggested that miR-940 directly targeted FOXO3. Moreover, we found that the effect of si-FOXO3 was rescued by miR-940 inhibitor in BC cells. miR-940 may promote the proliferation and invasion abilities of BC cells by targeting FOXO3. Our study suggested that miR-940 could be a novel molecular target for therapies against BC.

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“…EP300 encodes the repressor histone acetyltransferase protein p300, which also has roles as a transcriptional corepressor protein. EP300 has been implicated in modulation of FOXO3 activity (Mahmud et al 2019) and in Beta coefficients, p values and 95% confidence intervals (95% CI) are given for associations between circRNA expression and hand grip strength. Three hundred six individuals were assessed.…”

Section: Discussionmentioning

confidence: 99%

circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan

et al. 2019

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Circular RNAs (circRNAs) are an emerging class of non-coding RNA molecules that are thought to regulate gene expression and human disease. Despite the observation that circRNAs are known to accumulate in older organisms and have been reported in cellular senescence, their role in aging remains relatively unexplored. Here, we have assessed circRNA expression in aging human blood and followed up age-associated circRNA in relation to human aging phenotypes, mammalian longevity as measured by mouse median strain lifespan and cellular senescence in four different primary human cell types. We found that circRNAs circDEF6, circEP300, circFOXO3 and circFNDC3B demonstrate associations with parental longevity or hand grip strength in 306 subjects from the InCHIANTI study of aging, and furthermore, circFOXO3 and circEP300 also demonstrate differential expression in one or more human senescent cell types. Finally, four circRNAs tested showed evidence of conservation in mouse. Expression levels of one of these, circPlekhm1, was nominally associated with lifespan. These data suggest that circRNA may represent a novel class of regulatory RNA involved in the determination of aging phenotypes, which may show future promise as both biomarkers and future therapeutic targets for age-related disease.

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EP300 and SIRT1/6 Co-Regulate Lapatinib Sensitivity Via Modulating FOXO3-Acetylation and Activity in Breast Cancer

Cited by 34 publications

References 35 publications

Deciphering the Signaling Network Landscape of Breast Cancer Improves Drug Sensitivity Prediction

Deciphering the Signaling Network Landscape of Breast Cancer Improves Drug Sensitivity Prediction

MiR-940 promotes malignant progression of breast cancer by regulating FOXO3

circRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan

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