Differential optineurin expression controls <scp>TGFβ</scp> signaling and is a key determinant for metastasis of triple negative breast cancer

Liu, Sijia; Dinther, Maarten van; Hagenaars, Sophie C; Gu, Yuanzhuo; Kuipers, Thomas B.; Mei, Hailiang; Gomez‐Puerto, Maria Catalina; Mesker, Wilma E.; Dijke, Peter ten

doi:10.1002/ijc.34483

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…Research has shown that OPTN inhibits TGF-β signaling in TNBC (Triple negative breast cancer) cells by interacting with the TGF-β type I receptor (TβRI), leading to its ubiquitination and degradation. This mechanism suppresses metastasis by reducing EMT-associated factors 59 experimental findings in TM cells indicate that OPTN overexpression suppresses TGF-β signaling, whereas OPTN knockdown enhances TGF-β signaling and EMT. Furthermore, OPTN overexpression leads to FOXC1 ubiquitination, a process reversed by proteasomal inhibitors.…”

Section: Discussionmentioning

confidence: 93%

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TGF-β2/OPTN/FOXC1/miR-200axis regulates intraocular pressure dynamics in trabecular meshwork cells

Sugali,

Gajula,

Chava

et al. 2024

Preprint

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SummaryGlaucoma is the second leading cause of irreversible blindness globally, with elevated intraocular pressure (IOP) being its primary risk factor. Current therapeutic approaches, such as beta-blockers, alpha-adrenergic agonists, Rho-kinase inhibitors, etc., aim to reduce IOP levels. However, the molecular mechanisms underlying altered IOP remain poorly understood. In this study, we have treated primary human trabecular meshwork cells (HTM) with exogenous dexamethasone (dex) or transforming growth factor beta-2 (TGF-β2) to investigate its effects on glaucoma candidate genes. Interestingly, our findings reveal that FOXC1 acts as a repressor toCYP1B1, and optineurin (OPTN) facilitates the ubiquitination of FOXC1, thereby inducing CYP1B1 expression. Further, we discovered that themiR-200family and other miRNAs regulate these glaucoma-candidate genes. Furthermore, TGF-β2 downregulates themiR-200family, whereas themiR-200family targetsFOXC1, exerting reversible effects by altering the extracellular matrix. FOXC1 positively regulatesCLOCK, one of its target genes. Besides, CLOCK/BMAL1 has binding sites on miR-200 family promoters. Modulating the TGF-β2/OPTN/FOXC1/miR-200axis appears critical in regulating IOP dynamics through CLOCK/BMAL1-mediated daily rhythmicity in the anterior segment of the eye.Graphical Abstract

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

TGF-β2/OPTN/FOXC1/miR-200axis regulates intraocular pressure dynamics in trabecular meshwork cells

Sugali,

Gajula,

Chava

et al. 2024

Preprint

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“…However, a recent study challenges the necessity of PINK1 and PRKN for initiating mitophagy [ 87 ]. Consequently, it has been suggested that OPTN may have tumor suppressor functions by activating suppressor autophagy mediated by HACE1 , a tumor suppressor [ 88 , 89 , 90 ], or by repressing the pro-oncogenic transforming growth factor-β (TGFβ) signaling in triple-negative breast cancer (TNBC) cells, a subtype of BRCA [ 91 ]. Importantly, OPTN has been found to be downregulated in GBM tumor samples, which has been corroborated by independent studies [ 92 ].…”

Section: Clustering Solid Tumors Based On Autophagy-related Genesmentioning

confidence: 99%

Insights from a Computational-Based Approach for Analyzing Autophagy Genes across Human Cancers

Carrasco

Giovanini

Ramos

et al. 2023

Genes

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In the last decade, there has been a boost in autophagy reports due to its role in cancer progression and its association with tumor resistance to treatment. Despite this, many questions remain to be elucidated and explored among the different tumors. Here, we used omics-based cancer datasets to identify autophagy genes as prognostic markers in cancer. We then combined these findings with independent studies to further characterize the clinical significance of these genes in cancer. Our observations highlight the importance of innovative approaches to analyze tumor heterogeneity, potentially affecting the expression of autophagy-related genes with either pro-tumoral or anti-tumoral functions. In silico analysis allowed for identifying three genes (TBC1D12, KERA, and TUBA3D) not previously described as associated with autophagy pathways in cancer. While autophagy-related genes were rarely mutated across human cancers, the expression profiles of these genes allowed the clustering of different cancers into three independent groups. We have also analyzed datasets highlighting the effects of drugs or regulatory RNAs on autophagy. Altogether, these data provide a comprehensive list of targets to further the understanding of autophagy mechanisms in cancer and investigate possible therapeutic targets.

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CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation‐Mediated c‐Myc Deubiquitylation to Facilitate Mutant TP53 Transcription

Wang,

Li,

Yang

et al. 2024

Advanced Science

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Triple‐negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%–80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c‐Myc, further promoting the stability of c‐Myc via deacetylation‐mediated inhibition of K48‐linked ubiquitylation. Stably expressed c‐Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p‐AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD‐L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c‐Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

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Differential optineurin expression controls TGFβ signaling and is a key determinant for metastasis of triple negative breast cancer

Cited by 4 publications

References 47 publications

TGF-β2/OPTN/FOXC1/miR-200axis regulates intraocular pressure dynamics in trabecular meshwork cells

TGF-β2/OPTN/FOXC1/miR-200axis regulates intraocular pressure dynamics in trabecular meshwork cells

Insights from a Computational-Based Approach for Analyzing Autophagy Genes across Human Cancers

CircCFL1 Promotes TNBC Stemness and Immunoescape via Deacetylation‐Mediated c‐Myc Deubiquitylation to Facilitate Mutant TP53 Transcription

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