Stemness factor Sall4 is required for DNA damage response in embryonic stem cells

Xiong, Jie; Todorova, Dilyana; Su, Ning-Yuan; Kim, J.; Lee, P; Shen, Zhouxin; Briggs, Steven P.; Xu, Yang

doi:10.1084/jem.2123oia6

Cited by 15 publications

(19 citation statements)

References 13 publications

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“…In addition, Xiong et al. confirmed that, following irradiation, impaired autophosphorylation of ATM in Sall4 −/− embryonic stem cells (ESCs) are caused by the loss of SALL4 . Taken together, we hypothesized that SALL4 might regulate radiosensitivity via ATM/Chk2/p53 pathway in NPC.…”

Section: Introductionmentioning

confidence: 59%

“…In response to DNA damage, cells activate the sensor kinase ATM that in turn phosphorylates multiple downstream substrates, including Chk2 and p53, resulting in cell cycle checkpoint initiation and/or apoptosis . Since the efficient recruitment and activation of ATM are guaranteed by the interaction of SALL4 with Rad50 to stabilize the Mre11‐Rad50‐Nbs1 complex, it is reasonable to hypothesize that SALL4 could affect the radiosensitivity via ATM/Chk2/p53 pathway. In both CNE2 and CNE2R cells, with or without radiation exposure, SALL4 silencing vastly downregulated the phosphorylated variants of ATM, Chk2, and p53, and the anti‐apoptosis protein Bcl‐2.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal expression of SALL4 promotes tumorigenesis, invasion and metastasis through maintaining cancer stem cell properties . What's more, a recent study indicated that the stemness factor SALL4 was required for efficient recruitment and activation of Ataxia‐telangiectasia mutated kinase (ATM), which is the initiator of DNA damage response . Meanwhile, the inhibition of SALL4 could induce apoptosis and cell cycle arrest in several cancers .…”

Section: Introductionmentioning

confidence: 99%

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SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway

Nie

Guo

et al. 2019

Cancer Medicine

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Radiotherapy is the mainstay and primary curative treatment modality in nasopharyngeal carcinoma (NPC), whose efficacy is limited by the development of intrinsic and acquired radioresistance. Thus, deciphering new molecular targets and pathways is essential for enhancing the radiosensitivity of NPC. SALL4 is a vital factor in the development and prognosis of various cancers, but its role in radioresistance remains elusive. This study aimed to explore the association of SALL4 expression with radioresistance of NPC. It was revealed that SALL4 expression was closely correlated with advanced T classification of NPC patients. Inhibition of SALL4 reduced proliferation and sensitized cells to radiation both in vitro and in vivo. Furthermore, SALL4 silencing increased radiation‐induced DNA damage, apoptosis, and G2/M arrest in CNE2 and CNE2R cells. Moreover, knockdown of SALL4 impaired the expression of p‐ATM, p‐Chk2, p‐p53, and anti‐apoptosis protein Bcl‐2, while pro‐apoptosis protein was upregulated. These findings indicate that SALL4 could induce radioresistance via ATM/Chk2/p53 pathway and its downstream proteins related to apoptosis. Targeting SALL4 might be a promising approach for the development of novel radiosensitizing therapeutic agents for radioresistant NPC patients.

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Section: Introductionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway

Nie

Guo

et al. 2019

Cancer Medicine

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“…Furthermore, comparative transcriptome‐wide studies have characterized many DEGs with essential functions other than those we have stated above. For example, among the upregulated genes, spalt‐like transcription factor 4 (Sall4) rapidly moves to DNA double‐stranded break (DSB) sites after DNA damage and is required for activating the critical ataxia telangiectasia mutated (ATM)‐dependent cellular responses to DSBs, conferring resistance to DSB‐induced cytotoxicity in mouse ESCs (Xiong et al, ). In oocytes, Sall4 regulates the expression of the key histone demethylase coding genes Kdm5b, Kdm6a, and Kdm6b to modulate the H3K4me3 and H3K27me3 modifications that are critical for oocyte maturation and meiosis resumption (Xu et al, ).…”

Section: Discussionmentioning

confidence: 99%

Single xenotransplant of rat brown adipose tissue prolonged the ovarian lifespan of aging mice by improving follicle survival

et al. 2019

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Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long‐acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat‐to‐mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; IL6 and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.

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“…Accumulating data have demonstrated functional links between pluripotency and cancer. For example, pluripotency factors Nanog, Oct4, and Sall4 are frequently overexpressed in human cancers , and play important roles in promoting metastasis and drug resistance . Like pluripotent stem cells, tumor cells also rely on glycolysis for energy and substrate pools for biological synthesis .…”

Section: Resultsmentioning

confidence: 99%

IDO1 Maintains Pluripotency of Primed Human Embryonic Stem Cells by Promoting Glycolysis

et al. 2019

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Human embryonic stem cells (hESCs) depend on glycolysis for energy supply and pluripotency and switch to oxidative phosphorylation upon differentiation. The underlying mechanisms remain unclear. Here, we demonstrate that indoleamine 2,3-dioxygenase 1 (IDO1) is expressed in primed hESCs and its expression rapidly downregulated upon hESC differentiation. IDO1 is required to maintain pluripotency by suppressing mitochondria activity and promoting glycolysis through the increase of NAD + /NADH ratio. The upregulation of IDO1 during hESC differentiation suppresses the differentiation of hESCs into certain lineages of cells such as cardiomyocytes, which depend on oxidative phosphorylation to satisfy their high energy demand. Therefore, IDO1 plays important roles in maintaining the pluripotency of hESCs.Indoleamine 2,3-dioxygenase 1 (IDO1) has been known to play important metabolic roles in the kynurenine pathway. This study discovered that IDO1 is required to maintain glycolysis in human embryonic stem cells (hESCs), and therefore maintains pluripotency of hESCs. These findings further shed light on the link between pluripotency and cancer, since cancer cells have a similar metabolic process as stem cells.

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Stemness factor Sall4 is required for DNA damage response in embryonic stem cells

Cited by 15 publications

References 13 publications

SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway

SALL4 induces radioresistance in nasopharyngeal carcinoma via the ATM/Chk2/p53 pathway

Single xenotransplant of rat brown adipose tissue prolonged the ovarian lifespan of aging mice by improving follicle survival

IDO1 Maintains Pluripotency of Primed Human Embryonic Stem Cells by Promoting Glycolysis

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