CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis

Zhang, Zhao-Xiong; Zhang, Wan-Ni; Sun, Yuanyuan; Li, Yunhui; Xu, Zhonghua; Fu, Wei‐Neng

doi:10.2147/ott.s156582

Cited by 26 publications

(16 citation statements)

References 27 publications

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“…In aggregate, this response is consistent with Nox1-controlled CREB playing a vital role in regulating hypoxia-induced EC proliferation & cell progression and migration [59], [60], [61]. Indeed, hypoxia-induced EC proliferation and migration appear to be dependent on CREB-regulated Gremlin1 expression, the latter of which has been implicated in the development of PAH [62].…”

Section: Discussionsupporting

confidence: 71%

Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration

Jesus¹,

DeVallance²,

Li³

et al. 2019

Redox Biology

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Pulmonary arterial hypertension (PAH) is a complex degenerative disorder marked by aberrant vascular remodeling associated with hyperproliferation and migration of endothelial cells (ECs). Previous reports implicated bone morphogenetic protein antagonist Gremlin 1 in this process; however, little is known of the molecular mechanisms involved. The current study was designed to test whether redox signaling initiated by NADPH oxidase 1 (Nox1) could promote transcription factor CREB activation by redox factor 1 (Ref-1), transactivation of Gremlin1 transcription, EC migration, and proliferation. Human pulmonary arterial EC (HPAECs) exposed in vitro to hypoxia to recapitulate PAH signaling displayed induced Nox1 expression, reactive oxygen species (ROS) production, PKA activity, CREB phosphorylation, and CREB:CRE motif binding. These responses were abrogated by selective Nox1 inhibitor NoxA1ds and/or siRNA Nox1. Nox1-activated CREB migrated to the nucleus and bound to Ref-1 leading to CREB:CRE binding and Gremlin1 transcription. CHiP assay and CREB gene-silencing illustrated that CREB is pivotal for hypoxia-induced Gremlin1, which, in turn, stimulates EC proliferation and migration. In vivo , participation of Nox1, CREB, and Gremlin1, as well as CREB:CRE binding was corroborated in a rat PAH model. Activation of a previously unidentified Nox1-PKA-CREB/Ref-1 signaling pathway in pulmonary endothelial cells leads to Gremlin1 transactivation, proliferation and migration. These findings reveal a new signaling pathway by which Nox1 via induction of CREB and Gremlin1 signaling contributes to vascular remodeling and provide preclinical indication of its significance in PAH.

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Section: Discussionsupporting

confidence: 71%

Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration

Jesus¹,

DeVallance²,

Li³

et al. 2019

Redox Biology

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“…2). These different CREB activities result in increased tumor growth, resistance to antiproliferative signals, decreased apoptosis, enhanced angiogenesis, increased metabolism, and reduced immunogenicity [11][12][13][14][15][16][17][18].…”

Section: Function Of Creb As a Mediator Of Carcinogenesis: A General mentioning

confidence: 99%

What turns CREB on? And off? And why does it matter?

Steven

Friedrich

Jank

et al. 2020

Cell. Mol. Life Sci.

124

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Altered expression and function of the transcription factor cyclic AMP response-binding protein (CREB) has been identified to play an important role in cancer and is associated with the overall survival and therapy response of tumor patients. This review focuses on the expression and activation of CREB under physiologic conditions and in tumors of distinct origin as well as the underlying mechanisms of CREB regulation by diverse stimuli and inhibitors. In addition, the clinical relevance of CREB is summarized, including its use as a prognostic and/or predictive marker as well as a therapeutic target.

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“…Since CXCR2 and CCR2 are also expressed by M2 macrophages, we speculate that combination AZD1775 and AZD0156 treatment might impair M2 type polarization [27]. In addition, the involvement of Src and FAK in promoting cell migration and invasion is well known [28], and a recent report implicates a similar role for p-CREB [29]. Thus, our finding that expression of p-CREB, p-Src, p-Yes, and p-FAK are profoundly inhibited by WEE1 and ATM co-inhibition is consistent with a role for these molecules in PC cell migration.…”

Section: Discussionmentioning

confidence: 86%

Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

et al. 2020

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Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. Results In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3! serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. Conclusion Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken together, our results support further clinical development of DDR-targeting strategies for PC.

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CREB promotes laryngeal cancer cell migration via MYCT1/NAT10 axis

Cited by 26 publications

References 27 publications

Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration

Nox1/Ref-1-mediated activation of CREB promotes Gremlin1-driven endothelial cell proliferation and migration

What turns CREB on? And off? And why does it matter?

Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

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