Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Jiang, Ming; Zhou, Lei; Xu, Nan; An, Qing

doi:10.1111/1759-7714.13019

Cited by 43 publications

(29 citation statements)

References 62 publications

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“…As signature oncogenic pathways, PI3K/AKT and MAPK signaling pathways are important for almost every cancer type, including Ewing sarcoma ( 69–71 ). Our investigations (Figure 7 ) uncover novel epigenomic mechanisms for the activation of these pathways by CRC factors in Ewing sarcoma.…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Nucleic Acids Research

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Core regulatory circuitry (CRC)-dependent transcriptional network is critical for developmental tumors in children and adolescents carrying few gene mutations. However, whether and how CRC contributes to transcription regulation in Ewing sarcoma is unknown. Here, we identify and functionally validate a CRC ‘trio’ constituted by three transcription factors (TFs): KLF15, TCF4 and NKX2-2, in Ewing sarcoma cells. Epigenomic analyses demonstrate that EWS-FLI1, the primary fusion driver for this cancer, directly establishes super-enhancers of each of these three TFs to activate their transcription. In turn, KLF15, TCF4 and NKX2-2 co-bind to their own and each other's super-enhancers and promoters, forming an inter-connected auto-regulatory loop. Functionally, CRC factors contribute significantly to cell proliferation of Ewing sarcoma both in vitro and in vivo. Mechanistically, CRC factors exhibit prominent capacity of co-regulating the epigenome in cooperation with EWS-FLI1, occupying 77.2% of promoters and 55.6% of enhancers genome-wide. Downstream, CRC TFs coordinately regulate gene expression networks in Ewing sarcoma, controlling important signaling pathways for cancer, such as lipid metabolism pathway, PI3K/AKT and MAPK signaling pathways. Together, molecular characterization of the oncogenic CRC model advances our understanding of the biology of Ewing sarcoma. Moreover, CRC-downstream genes and signaling pathways may contain potential therapeutic targets for this malignancy.

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Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Nucleic Acids Research

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“…ERK and PI3K/AKT signaling pathways can promote growth, migration, and invasion of NSCLC [41,42]. Our previous studies also demonstrated that HPV-16 E7 oncoprotein promoted the activation of ERK1/2 and PI3K/AKT pathways in A549 and NCI-H460 cells [33,43].…”

Section: Maoa Played a Role In Hpv-16 E7-activated Erk1/2 But Not Aktmentioning

confidence: 65%

The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells

Huang¹,

Zhou²,

Liu³

et al. 2020

Int. J. Biol. Sci.

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Our previous studies have found that human papillomavirus (HPV)-16 E7 oncoprotein promotes epithelial-mesenchymal transition (EMT) and hypoxia-inducible factor-1α (HIF-1α) protein accumulation in non-small cell lung cancer (NSCLC) cells and monoamine oxidase A (MAOA) is highly expressed in NSCLC tissues. Here, we further explored the role of MAOA in HPV-16 E7-induced EMT and HIF-1α protein accumulation in A549 and NCI-H460 NSCLC cells. Our results showed that HPV-16 E7 enhanced MAOA expression in NSCLC cells. Additionally, MAOA knockout inhibited HPV-16 E7-induced migration, invasion, and EMT, and significantly reduced HPV-16 E7-induced ROS generation and HIF-1α protein accumulation via promoting its degradation. Furthermore, MAOA knockout suppressed HPV-16 E7-induced ERK1/2 activation. In vivo, MAOA knockout inhibited tumor growth, metastasis, and the expression of EMT-related markers and HIF-1α proteins induced by HPV-16 E7 in NCI-H460 NSCLC subcutaneous xenograft and in situ intrapulmonary models of nude mice. Taken together, our findings provide evidence that MAOA plays a key role in EMT and HIF-1α protein accumulation induced by HPV-16 E7 in NSCLC cells, suggesting that MAOA may be a potential therapeutic target for HPV-related NSCLC.

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“…As signature oncogenic pathways, PI3K/AKT and MAPK signaling pathways are important for almost every cancer type, including Ewing sarcoma (55–57). Our investigations (Fig.…”

Section: Discussionmentioning

confidence: 99%

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

Shi

Zheng

Jiang

et al. 2020

Preprint

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29Core regulatory circuitry (CRC)-dependent transcriptional network is critical for 30 developmental tumors in children and young adults carrying few gene mutations. 31 Ewing sarcoma resembles these developmental cancers in terms of having both 87 few genomic alterations and a single epigenomic driver, we postulated that such 88 oncogenic CRC model might exist in Ewing sarcoma, to cooperate with the 89 transcriptional function of EWS-FLI1. The current study was aimed to identify 90 and characterize this CRC apparatus in Ewing sarcoma, and to elucidate its 91 functional significance in this cancer. 92 93 94 5 / 46 Results 95 96 We recently characterized the super-enhancer landscape in Ewing sarcoma and 97 confirmed the essential role of EWS-FLI1 in regulating the epigenome of this 98 cancer (11). As introduced earlier, considering that CRC is particularly important 99 for childhood developmental cancers having few genomic lesions, we postulated 100 that such CRC model might also contribute to regulating Ewing sarcoma 101 transcriptome through either cooperating with or mediating the function of EWS-102 FLI1. To test this hypothesis, we first sought to identify mathematically master 103 TFs with high inter-connectivity through binding to their super-enhancers by 104 motif scanning using our established method (18, 24, 25). Because of the central 105 role of EWS-FLI1 in establishing the enhancer landscape in Ewing sarcoma, we 106 made significant modifications of the method by requiring that all candidate TFs 107 have both EWS-FLI1 binding motif and binding peaks in their assigned super-108 enhancers. We initially focused on the A673 cell line, since it is a well-109 characterized Ewing sarcoma line with available H3K27ac and EWS-FLI1 ChIP-110 Seq results (7). As a result, a small set (n=9) of CRC candidates were identified 111 (Fig. 1A), including NKX2-2 and FOS which are known functional cooperators 112 of EWS-FLI1 (7, 26). Because CRC factors have high and specific expression in 113 their corresponding cell types, we interrogated the Cancer Cell Line Encyclopedia 114 (CCLE) dataset and noted that, compared with other 5 CRC candidates (NFATC2, 115 FOS, IRF2, ZBTB7B and MEF2D, Supplement Fig. 1), the expression of 4 116 6 / 46 candidate TFs (KLF15, NKX2-2, TCF4 and RREB1) showed restricted 117 expression pattern in Ewing sarcoma cell lines (defined as top 5 among all cell 118 types, Fig. 1B). However, it should be noted that the specificity of RREB1 119 expression was overall poor, as most cancer types had comparable mRNA levels. Identification of CRC under the regulation of EWS-FLI1 in Ewing sarcoma 120As a parallel analysis, Pearson correlation coefficient of the mRNA levels of 121 these 9 candidates was determined, considering the co-regulatory relationship 122 between CRC members. Notably, the same set of 4 factors (KLF15, NKX2-2, 123 TCF4 and RREB1) displayed strong positive correlations with each other (Fig. 124 1C). In contrast, this correlation pattern was much weaker in other non-Ewing 125 sarco...

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Hydroxysafflor yellow A inhibited lipopolysaccharide‐induced non‐small cell lung cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT/mTOR and ERK/MAPK signaling pathways

Cited by 43 publications

References 62 publications

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

The role of monoamine oxidase A in HPV-16 E7-induced epithelial-mesenchymal transition and HIF-1α protein accumulation in non-small cell lung cancer cells

EWS-FLI1 regulates and cooperates with core regulatory circuitry in Ewing sarcoma

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