The oncogene c-Jun impedes somatic cell reprogramming

Liu, Jing; Han, Qingkai; Peng, Tianran; Peng, Mingying; Wei, Bei; Li, Dongwei; Wang, Xiaoshan; Yu, Shengyong; Yang, Jiaqi; Cao, Shuiyan; Huang, Kainian; Hutchins, Andrew P.; He, Li; Kuang, Jinqiang; Zhou, Zhiwei; Chen, Jing; Wu, Haoyu; Guo, Lin; Chen, Yongqiang; Chen, You; Li, Xuejia; Wu, Hongling; Liao, Baojian; He, Wei; Sui, Hong; Yao, Hongjie; Pan, Guangjin; Chen, Jiekai; Pei, Duanqing

doi:10.1038/ncb3193

Cited by 125 publications

(143 citation statements)

References 68 publications

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“…Liu et al reported that c-JUN induces the EMT process and directly activates a group of genes including TWIST2, TGM2, DUSP5 and ETS1 [39]. In agreement with this report, these four genes are down-regulated after ectopic SPANXA expression.…”

Section: Discussionsupporting

confidence: 89%

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

Hsiao

Hsu

et al. 2016

Oncotarget

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SPANXA (Sperm Protein Associated with the Nucleus on the X-chromosome, family members A1/A2) acts as a cancer-testis antigen expressed in normal testes, but dysregulated in various tumors. We found that SPANXA is highly expressed in low-invasive CL1-0 cells compared with isogenous high-invasive CL1-5 cells. SPANXA was preferably expressed in tumor tissues and associated with the prolonged survival of lung adenocarcinomas. SPANXA suppressed the invasion and metastasis of lung cancer cells in vitro and in vivo. By the expression microarray and pathway analysis, we found that the SPANXA-altered genes were enriched in the epithelial–mesenchymal transition (EMT) pathway. SPANXA reduced SNAI2 expression resulted in up-regulating E-cadherin. c-JUN acts as the positive-regulator of EMT. Silencing SPANXA increased c-JUN mRNA expression and blockage of c-JUN led to SNAI2 down-regulation. Our results clearly characterized SPANXA as an EMT inhibitor by suppressing c-JUN-SNAI2 axis in lung adenocarcinoma.

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Section: Discussionsupporting

confidence: 89%

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

Hsiao

Hsu

et al. 2016

Oncotarget

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“…Our results are in apparent disagreement with the recent study by Liu et al ., that suggested an inhibitory role for c-JUN in reprogramming [21]. There are several differences between our study and the study by Liu et al , including the choice of cells and reprogramming conditions.…”

Section: Discussionmentioning

confidence: 56%

MBD3 inhibits formation of liver cancer stem cells

Han

et al. 2016

Oncotarget

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Liver cancer cells can be reprogrammed into induced cancer stem cells (iCSCs) by exogenous expression of the reprogramming transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM). The nucleosome remodeling and deacetylase (NuRD) complex is essential for reprogramming somatic cells. In this study, we investigated the function of NuRD in the induction of liver CSCs. We showed that suppression of methyl-CpG binding domain protein 3 (MBD3), a core subunit of the NuRD repressor complex, together with OSKM transduction, induces conversion of liver cancer cells into stem-like cells. Expression of the transcription factor c-JUN is increased in MBD3-depleted iCSCs, and c-JUN activates endogenous pluripotent genes and regulates iCSC-related genes. These results indicate that MBD3/NuRD inhibits the induction of iCSCs, while c-JUN facilitates the generation of CSC-like properties. The iCSC reprogramming approach devised here provides a novel platform for dissection of the disordered signaling in liver CSCs. In addition, our results indicate that c-JUN may serve as a potential target for liver cancer therapy.

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“…These data suggested that Fra1 loss from MEs is critical for their silencing and iPSC production. Overexpression of cJun, the binding partner of Fra1, was also detrimental for reprogramming (Fig 5H, S6M) (Liu et al, 2015) and produced similar expression changes as Fra1 overexpression (Fig 5J/K), suggesting that cJun may block reprogramming in synergy with Fra1.…”

Section: Resultsmentioning

confidence: 91%

Cooperative Binding of Transcription Factors Orchestrates Reprogramming

Chronis

Fiziev

Papp

et al. 2017

Cell

477

611

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Summary Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription-factors (TFs), and chromatin-states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic-enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic-enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic-TF Fra1. Pluripotency-enhancer selection is a step-wise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency-enhancers are selected later and require OS and other pluripotency TFs. Somatic and pluripotency-TFs modulate reprogramming efficiency when overexpressed by altering OSK-targeting, somatic-enhancer inactivation, and pluripotency-enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific-TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.

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The oncogene c-Jun impedes somatic cell reprogramming

Cited by 125 publications

References 68 publications

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

MBD3 inhibits formation of liver cancer stem cells

Cooperative Binding of Transcription Factors Orchestrates Reprogramming

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