ZNF384–ZEB1 feedback loop regulates breast cancer metastasis

Meng, Qingxiang; Wang, Kenie; Li, Junhui; Zhang, Hui; Chen, Zhaohui; Zhou, Xue-Jie; Cao, Xuchen; Wang, Ping; Yu, Yue

doi:10.1186/s10020-022-00541-1

Cited by 7 publications

(6 citation statements)

References 39 publications

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“…It is reported that overexpression of ZNF384 has oncogenic potential for some solid tumors, such as hepatocellular carcinoma and breast cancer. 22 , 23 Because Z‐fusion proteins contain all of ZNF384, it is expected that the DNA binding sites are quite similar between them.…”

Section: Discussionmentioning

confidence: 99%

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

Yamada,

Okada,

Odaira

et al. 2024

Cancer Medicine

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BackgroundZNF384‐fusion (Z‐fusion) genes were recently identified in B‐cell acute lymphoblastic leukemia (B‐ALL) and are frequent in Japanese adult patients. The frequency is about 20% in those with Philadelphia chromosome‐negative B‐ALL. ZNF384 is a transcription factor and Z‐fusion proteins have increased transcriptional activity; however, the detailed mechanisms of leukemogenesis of Z‐fusion proteins have yet to be clarified.MethodsWe established three transfectants of cell lines expressing different types of Z‐fusion proteins, and analyzed their gene expression profile (GEP) by RNA‐seq. We also analyzed the GEP of clinical ALL samples using our previous RNA‐seq data of 323 Japanese ALL patients. We selected upregulated genes in both Z‐fusion gene‐expressing transfectants and Z‐fusion gene‐positive ALL samples, and investigated the binding of Z‐fusion proteins to regulatory regions of the candidate genes by ChIP‐qPCR.ResultsWe selected six commonly upregulated genes. After the investigation by ChIP‐qPCR, we finally identified CREB5 and RGS1 as direct and common target genes. RGS1 is an inhibitor of CXCL12‐CXCR4 signaling that is required for the homing of hematopoietic progenitor cells to the bone marrow microenvironment and development of B cells. Consistent with this, Z‐fusion gene transfectants showed impaired migration toward CXCL12.ConclusionsWe identified CREB5 and RGS1 as direct and common transcriptional targets of Z‐fusion proteins. The present results provide novel insight into the aberrant transcriptional regulation by Z‐fusion proteins.

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Section: Discussionmentioning

confidence: 99%

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

Yamada,

Okada,

Odaira

et al. 2024

Cancer Medicine

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“…Studies have explored a possible cancer-promoting activity of the transcription factor ZNF384 in different cancers. Meng et al showed that ZNF384 is upregulated in breast cancer and is important for cancer cell metastasis [ 36 ]. ZNF384 is possible transcription factor for the histone acetyltransferase HBO1, the latter promoted osteosarcoma cell growth in vitro and in vivo [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpressed Gαi1 exerts pro-tumorigenic activity in nasopharyngeal carcinoma

Yin,

Zhang,

Teng

et al. 2023

Cell Death Dis

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The current study tested the expression and potential functions of Gαi1 in nasopharyngeal carcinoma (NPC). The Cancer Genome Atlas (TCGA) database results demonstrate that Gαi1 transcripts’ number in NPC tissues is significantly higher than that in the normal nasal epithelial tissues. Its overexpression correlates with poor survival in certain NPC patients. Moreover, Gαi1 is significantly upregulated in NPC tissues of local primary patients and in different primary human NPC cells. Whereas its expression is relatively low in cancer-surrounding normal tissues and in primary nasal epithelial cells. Genetic silencing (via shRNA strategy) or knockout (via CRISPR-sgRNA method) of Gαi1 substantially suppressed viability, proliferation, cell cycle progression, and migration in primary NPC cells, causing significant caspase-apoptosis activation. Contrarily, ectopic Gαi1 expression exerted pro-tumorigenic activity and strengthened cell proliferation and migration in primary NPC cells. Gαi1 is important for Akt-mTOR activation in NPC cells. Akt-S6K phosphorylation was downregulated after Gαi1 shRNA or KO in primary NPC cells, but strengthened following Gαi1 overexpression. In Gαi1-silenced primary NPC cells, a S473D constitutively-active mutant Akt1 (caAkt1) restored Akt-S6K phosphorylation and ameliorated Gαi1 shRNA-induced proliferation inhibition, migration reduction and apoptosis. Bioinformatics analyses proposed zinc finger protein 384 (ZNF384) as a potential transcription factor of Gαi1. In primary NPC cells, ZNF384 shRNA or knockout (via CRISPR-sgRNA method) decreased Gαi1 mRNA and protein expression, whereas ZNF384 overexpression upregulated it. Importantly, there was an increased binding between ZNF384 protein and the Gαi1 promoter in human NPC tissues and different NPC cells. In vivo studies showed that intratumoral injection of Gαi1-shRNA-expressing adeno-associated virus (AAV) impeded subcutaneous NPC xenograft growth in nude mice. Gαi1 downregulation, Akt-mTOR inactivation, and apoptosis induction were detected in Gαi1-silenced NPC xenograft tissues. Gαi1 KO also effectively inhibited the growth of NPC xenografts in nude mice. Together, overexpressed Gαi1 exerts pro-tumorigenic activity in NPC possibly by promoting Akt-mTOR activation.

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“…Cell proliferation was measured using the CCK-8 kit (Yeasen, Shanghai, China) as previously described 34 .…”

Section: Cell Counting Kit-8 (Cck-8) Assays Of Cell Viabilitymentioning

confidence: 99%

PKMYT1 Promotes Epithelial-Mesenchymal Transition Process in Triple-Negative Breast Cancer by Activating Notch Signaling

Li,

Huang,

Ruan

2024

RIC

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Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/ threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling. (REV INVEST CLIN.

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ZNF384–ZEB1 feedback loop regulates breast cancer metastasis

Cited by 7 publications

References 39 publications

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

RGS1 and CREB5 are direct and common transcriptional targets of ZNF384‐fusion proteins

Overexpressed Gαi1 exerts pro-tumorigenic activity in nasopharyngeal carcinoma

PKMYT1 Promotes Epithelial-Mesenchymal Transition Process in Triple-Negative Breast Cancer by Activating Notch Signaling

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