Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers

Yuxiong, Wang; Faping, Li; Bin, Liu; Yanghe, Zhang; Yao, Li; Yunkuo, Li; Yishu, Wang; Honglan, Zhou

doi:10.1016/j.biopha.2023.115335

Cited by 9 publications

(5 citation statements)

References 185 publications

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“… 17 Aberrant expression of CREB3 has been observed in diverse cancer types such as breast and bladder cancers, which can affect tumour progression and metastasis. 18 Nonetheless, the precise involvement of CREB3 in GC remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…CREB3 is located on the endoplasmic reticulum membrane and contains five family members (CREB3 and its homologues CREB3L1, CREB3L2, CREB3L3 and CREB3L4), which primarily exert influence on cellular metabolic processes 17 . Aberrant expression of CREB3 has been observed in diverse cancer types such as breast and bladder cancers, which can affect tumour progression and metastasis 18 . Nonetheless, the precise involvement of CREB3 in GC remains to be elucidated.…”

Section: Resultsmentioning

confidence: 99%

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Single‐cell analysis uncovers high‐proliferative tumour cell subtypes and their interactions in the microenvironment of gastric cancer

Zhang,

Wang,

Dong

et al. 2024

J Cellular Molecular Medi

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Gastric cancer (GC) remains a prominent malignancy that poses a significant threat to human well‐being worldwide. Despite advancements in chemotherapy and immunotherapy, which have effectively augmented patient survival rates, the mortality rate associated with GC remains distressingly high. This can be attributed to the elevated proliferation and invasive nature exhibited by GC. Our current understanding of the drivers behind GC cell proliferation remains limited. Hence, in order to reveal the molecular biological mechanism behind the swift advancement of GC, we employed single‐cell RNA‐sequencing (scRNA‐seq) to characterize the tumour microenvironment in this study. The scRNA‐seq data of 27 patients were acquired from the Gene Expression Omnibus database. Differential gene analysis, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis were employed to investigate 38 samples. The copy number variation level exhibited by GC cells was determined using InferCNV. The CytoTRACE, Monocle and Slingshot analysis were used to discern the cellular stemness and developmental trajectory of GC cells. The CellChat package was utilized for the analysis of intercellular communication crosstalk. Moreover, the findings of the data analysis were validated through cellular functional tests conducted on the AGS cell line and SGC‐7901 cell line. Finally, this study constructed a risk scoring model to evaluate the differences of different risk scores in clinical characteristics, immune infiltration, immune checkpoints, functional enrichment, tumour mutation burden and drug sensitivity. Within the microenvironment of GC, we identified the presence of 8 cell subsets, encompassing NK_T cells, B_Plasma cells, epithelial cells, myeloid cells, endothelial cells, mast cells, fibroblasts, pericytes. By delving deeper into the characterization of GC cells, we identified 6 specific tumour cell subtypes: C0 PSCA+ tumour cells, C1 CLDN7+ tumour cells, C2 UBE2C+ tumour cells, C3 MUC6+ tumour cells, C4 CHGA+ tumour cells and C5 MUC2+ tumour cells. Notably, the C2 UBE2C+ tumour cells demonstrated a close association with cell mitosis and the cell cycle, exhibiting robust proliferative capabilities. Our findings were fortified through enrichment analysis, pseudotime analysis and cell communication analysis. Meanwhile, knockdown of the transcription factor CREB3, which is highly active in UBE2C+ tumour cells, significantly impedes the proliferation, migration and invasion of GC cells. And the prognostic score model constructed with CREB3‐related genes showcased commendable clinical predictive capacity, thus providing valuable guidance for patients' prognosis and clinical treatment decisions. We have identified a highly proliferative cellular subgroup C2 UBE2C+ tumour cells in GC for the first time. The employment of a risk score model, which is based on genes associated with UBE2C expression, exhibits remarkable proficiency in predicting the prognosis of GC patients. In our investigation, we observed that the knockdown of the transcription factor CREB3 led to a marked reduction in cellular proliferation, migration and invasion in GC cell line models. Implementing a stratified treatment approach guided by this model represents a judicious and promising methodology.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Single‐cell analysis uncovers high‐proliferative tumour cell subtypes and their interactions in the microenvironment of gastric cancer

Zhang,

Wang,

Dong

et al. 2024

J Cellular Molecular Medi

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“…By transcriptome analysis of Hs 578T cells, we identified NRF2 target genes downstream of Cyss uptake. The DEGs with known function that are positively regulated by Cyss deprivation in an NRF2-dependent manner are stress response genes involved in endoplasmic reticulum (ER) stress response and autophagy ( DDIT4 , CREB3L4 , DDIT3 , XAF1 , NUPR1, and GADD45B ) [ 32 – 36 ], mitophagy ( MORN4 ) [ 37 ] or mitochondrial biogenesis ( TFB1M ) [ 38 ]. Since NRF2 is a transcriptional activator, we hypothesize that these genes are rapidly activated by OS and ER stress induced by Cyss deprivation and are only indirectly regulated by NRF2 as it plays a role in balancing OS, mitochondrial dysfunction and also ER stress [ 39 , 40 ] Of the 22 DEGs that were negatively regulated by Cyss deprivation and positively regulated by exogenously expressed NRF2, 19 remained upregulated in the presence of exogenously expressed NRF2 even in the absence of Cyss and consequently could be direct targets of NRF2 transcriptional activity and involved in the survival of Hs 578T cells under these conditions.…”

Section: Discussionmentioning

confidence: 99%

NRF2 activation by cysteine as a survival mechanism for triple-negative breast cancer cells

Bottoni,

Minetti,

Realini

et al. 2024

Oncogene

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Triple-negative breast cancer (TNBC) is a very aggressive and heterogeneous group of tumors. In order to develop effective therapeutic strategies, it is therefore essential to identify the subtype-specific molecular mechanisms underlying disease progression and resistance to chemotherapy. TNBC cells are highly dependent on exogenous cystine, provided by overexpression of the cystine/glutamate antiporter SLC7A11/xCT, to fuel glutathione synthesis and promote an oxidative stress response consistent with their high metabolic demands. Here we show that TNBC cells of the mesenchymal stem-like subtype (MSL) utilize forced cystine uptake to induce activation of the transcription factor NRF2 and promote a glutathione-independent mechanism to defend against oxidative stress. Mechanistically, we demonstrate that NRF2 activation is mediated by direct cysteinylation of the inhibitor KEAP1. Furthermore, we show that cystine-mediated NRF2 activation induces the expression of important genes involved in oxidative stress response, but also in epithelial-to-mesenchymal transition and stem-like phenotype. Remarkably, in survival analysis, four upregulated genes (OSGIN1, RGS17, SRXN1, AKR1B10) are negative prognostic markers for TNBC. Finally, expression of exogenous OSGIN1, similarly to expression of exogenous NRF2, can prevent cystine depletion-dependent death of MSL TNBC cells. The results suggest that the cystine/NRF2/OSGIN1 axis is a potential target for effective treatment of MSL TNBCs.

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“…Effects of CREB3 family on diseases and their regulatory mechanisms vary obviously in different environment. 13 For example, CREB3L3, also known as CREBH, was supposed to regulate hepatic metabolism through transactivating peroxisome proliferator activated receptor α and liver X receptor α. CREB3L1 was associated with extracellular matrix regulation and chondrogenesis. 14 CREB3 was reported to have effects on progression of several cancers.…”

Section: Introductionmentioning

confidence: 99%

“…cAMP responsive element binding protein 3 (CREB3) is a member of transcription factor (TF) bZIP family, which includes CREB3, cAMP responsive element binding protein 3 like (CREB3L) 1, CREB3L2, CREB3L3, and CREB3L4. Effects of CREB3 family on diseases and their regulatory mechanisms vary obviously in different environment 13 . For example, CREB3L3, also known as CREBH, was supposed to regulate hepatic metabolism through transactivating peroxisome proliferator activated receptor α and liver X receptor α. CREB3L1 was associated with extracellular matrix regulation and chondrogenesis 14 .…”

Section: Introductionmentioning

confidence: 99%

CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA‐binding motif protein 38

He,

Han,

et al. 2024

MedComm

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AbstractcAMP responsive element binding protein 3 (CREB3), belonging to bZIP family, was reported to play multiple roles in various cancers, but its role in hepatocellular carcinoma (HCC) is still unclear. cAMP responsive element binding protein 3 like 3 (CREB3L3), another member of bZIP family, was thought to be transcription factor (TF) to regulate hepatic metabolism. Nevertheless, except for being TFs, other function of bZIP family were poorly understood. In this study, we found CREB3 inhibited growth and metastasis of HCC in vitro and in vivo. RNA sequencing indicated CREB3 regulated AKT signaling to influence HCC progression. Mass spectrometry analysis revealed CREB3 interacted with insulin receptor (INSR). Mechanistically, CREB3 suppressed AKT phosphorylation by inhibiting the interaction of INSR with insulin receptor substrate 1 (IRS1). In our study, CREB3 was firstly proved to affect activation of substrates by interacting with tyrosine kinase receptor. Besides, CREB3 could act as a TF to transactivate RNA‐binding motif protein 38 (RBM38) expression, leading to suppressed AKT phosphorylation. Rescue experiments further confirmed the independence between the two functional manners. In conclusion, CREB3 acted as a tumor suppressor in HCC, which inhibited AKT phosphorylation through independently interfering interaction of INSR with IRS1, and transcriptionally activating RBM38.

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Regulatory mechanisms of the cAMP-responsive element binding protein 3 (CREB3) family in cancers

Cited by 9 publications

References 185 publications

Single‐cell analysis uncovers high‐proliferative tumour cell subtypes and their interactions in the microenvironment of gastric cancer

Single‐cell analysis uncovers high‐proliferative tumour cell subtypes and their interactions in the microenvironment of gastric cancer

NRF2 activation by cysteine as a survival mechanism for triple-negative breast cancer cells

CREB3 suppresses hepatocellular carcinoma progression by depressing AKT signaling through competitively binding with insulin receptor and transcriptionally activating RNA‐binding motif protein 38

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