Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities

Dinh, Timothy A.; Sritharan, Ramja; Smith, F. Donelson; Francisco, Adam B.; Rosanna, K.; Bunaciu, Rodica P.; Kanke, Matt; Danko, Charles G.; Massa, Andrew P; Scott, John D.; Sethupathy, Praveen

doi:10.1016/j.celrep.2020.03.073

Cited by 33 publications

(82 citation statements)

References 92 publications

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“…Similarly, the key transcriptional mediators of the effects of c-MYC and n-MYC on cell growth in FLX1 cells and in FLC remain unknown. Moreover, the extent to which MYC may interact with other key transcription factors such as CRTC2 (Hollstein et al, 2019) or AP-1/CREB (Dinh et al, 2020) unknown. Thus, our discovery of this new means of PKA-responsive MYC activation warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Chan

Maisel

Hwang

et al. 2021

Preprint

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Genetic alterations that activate protein kinase A (PKA) signaling are found across many tumor types, but their downstream oncogenic mechanisms are poorly understood. We used global phosphoproteomics and kinome activity profiling to map the conserved signaling outputs driven by diverse genetic changes that activate PKA in human cancer, including melanoma and fibrolamellar carcinoma (FLC). We define two consensus networks of effectors downstream of PKA in cancer models. One is centered on RAS/MAPK components, and a second involves Aurora Kinase A (AURKA). We find that AURKA stabilizes c-MYC and n-MYC protein levels and expression programs in PKA-dependent tumor models, in part via a positive feedback loop mediated by the oncogenic kinase PIM2. This process can be suppressed by conformation-disrupting AURKA inhibitors such as CD-532. Our findings elucidate two independent mechanisms of PKA-driven tumor cell growth and offer insight into drug targets for study in FLC and other PKA-dependent malignancies.

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Section: Discussionmentioning

confidence: 99%

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Chan

Maisel

Hwang

et al. 2021

Preprint

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“…All 15 datasets, including our and other bulk RNA-seq, scRNAseq, and microRNA-seq data, were collected from the Gene Expression Omnibus (GEO) database with processed series matrix files 1 . Six of our previous published datasets were used, including GSE73114 (Oikawa et al, 2015), GSE114974 (Dinh et al, 2019;Dinh et al, 2020), GSE101133 (Yan et al, 2017), GSE75141 (Wu et al, 2017), GSE105019 (Fu et al, 2019), and GSE116113 (Fu et al, 2019). Nine datasets from other teams were all used to validate the results in this work.…”

Section: Data Sourcementioning

confidence: 99%

“…Our previous study has achieved the RNA-seq and microRNAseq of four stages during the maturation of hepatic lineage, including hBTSCs, hHpSCs, hHBs, and hAHeps (Oikawa et al, 2015;Dinh et al, 2019Dinh et al, , 2020. In order to explore the key microRNAs and mRNAs during the development from hBTSCs to hAHeps, bioinformatic analyses were performed in both the RNA-seq and microRNA-seq, and validation of the results have been comprehensively performed following our work flowchart (Figure 1A).…”

Section: Mirnas Were Gradually Downregulated Following the Hepatic Mamentioning

confidence: 99%

A MicroRNA-Based Network Provides Potential Predictive Signatures and Reveals the Crucial Role of PI3K/AKT Signaling for Hepatic Lineage Maturation

Wang

Zhang

Yang

et al. 2021

Front. Cell Dev. Biol.

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BackgroundFunctions of miRNAs involved in tumorigenesis are well reported, yet, their roles in normal cell lineage commitment remain ambiguous. Here, we investigated a specific “transcription factor (TF)-miRNA-Target” regulatory network during the lineage maturation of biliary tree stem cells (BTSCs) into adult hepatocytes (hAHeps).MethodBioinformatic analysis was conducted based on our RNA-seq and microRNA-seq datasets with four human hepatic-lineage cell lines, including hBTSCs, hepatic stem cells (hHpSCs), hepatoblasts (hHBs), and hAHeps. Short time-series expression miner (STEM) analysis was performed to reveal the time-dependent dynamically changed miRNAs and mRNAs. GO and KEGG analyses were applied to reveal the potential function of key miRNAs and mRNAs. Then, the miRDB, miRTarBase, TargetScan, miRWalk, and DIANA-microT-CDS databases were adopted to predict the potential targets of miRNAs while the TransmiR v2.0 database was used to obtain the experimentally supported TFs that regulate miRNAs. The TCGA, Kaplan–Meier Plotter, and human protein atlas (HPA) databases and more than 10 sequencing data, including bulk RNA-seq, microRNA-seq, and scRNA-seq data related to hepatic development or lineage reprogramming, were obtained from both our or other published studies for validation.ResultsSTEM analysis showed that during the maturation from hBTSCs to hAHeps, 52 miRNAs were downwardly expressed and 928 mRNA were upwardly expressed. Enrichment analyses revealed that those 52 miRNAs acted as pluripotency regulators for stem cells and participated in various novel signaling pathways, including PI3K/AKT, MAPK, and etc., while 928 mRNAs played important roles in liver-functional metabolism. With an extensive sorting of those key miRNAs and mRNAs based on the target prediction results, 23 genes were obtained which not only functioned as the targets of 17 miRNAs but were considered critical for the hepatic lineage commitment. A “TF-miRNA-Target” regulatory network for hepatic lineage commitment was therefore established and had been well validated by various datasets. The network revealed that the PI3K/AKT pathway was gradually suppressed during the hepatic commitment.ConclusionA total of 17 miRNAs act as suppressors during hepatic maturation mainly by regulating 23 targets and modulating the PI3K/AKT signaling pathway. The regulatory network uncovers possible signatures and guidelines enabling us to identify or obtain the functional hepatocytes for future study.

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“…ChRO-seq represents the newest generation of nascent RNA sequencing technologies, and overcomes several limitations of previous versions including global run-on sequencing (GRO-seq) ( 21 ) and precision run-on sequencing (PRO-seq) ( 22 ). ChRO-seq was very recently successfully applied to archived solid tumor tissues ( 20 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

Chromatin regulatory dynamics of early human small intestinal development using a directed differentiation model

Hung

Dame

et al. 2021

Nucleic Acids Research

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The establishment of the small intestinal (SI) lineage during human embryogenesis ensures functional integrity of the intestine after birth. The chromatin dynamics that drive SI lineage formation and regional patterning in humans are essentially unknown. To fill this knowledge void, we apply a cutting-edge genomic technology to a state-of-the-art human model of early SI development. Specifically, we leverage chromatin run-on sequencing (ChRO-seq) to define the landscape of active promoters, enhancers and gene bodies across distinct stages of directed differentiation of human pluripotent stem cells into SI spheroids with regional specification. Through comprehensive ChRO-seq analysis we identify candidate stage-specific chromatin activity states, novel markers and enhancer hotspots during the directed differentiation. Moreover, we propose a detailed transcriptional network associated with SI lineage formation or regional patterning. Our ChRO-seq analyses uncover a previously undescribed pattern of enhancer activity and transcription at HOX gene loci underlying SI regional patterning. We also validated this unique HOX dynamics by the analysis of single cell RNA-seq data from human fetal SI. Overall, the results lead to a new proposed working model for the regulatory underpinnings of human SI development, thereby adding a novel dimension to the literature that has relied almost exclusively on non-human models.

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Hotspots of Aberrant Enhancer Activity in Fibrolamellar Carcinoma Reveal Candidate Oncogenic Pathways and Therapeutic Vulnerabilities

Cited by 33 publications

References 92 publications

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism

A MicroRNA-Based Network Provides Potential Predictive Signatures and Reveals the Crucial Role of PI3K/AKT Signaling for Hepatic Lineage Maturation

Chromatin regulatory dynamics of early human small intestinal development using a directed differentiation model

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