Poly(ADP-ribosyl)ation of OVOL2 regulates aneuploidy and cell death in cancer cells

Zhang, Rui; Hong, Jing-Jing; Yang, Qiaoyun; Ong, Chin‐Tong; Li, Boan; Liou, Yih‐Cherng

doi:10.1038/s41388-018-0615-3

Cited by 8 publications

(5 citation statements)

References 49 publications

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“…This evidence underscored a previously unknown function of OVOL2 in cancer. Indeed, some works reported an association of OVOL2 with inhibition of cancer cells' proliferation, but no mechanistic details or functional validation have been provided so far [ 37 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Gugnoni

Manzotti

Vitale

et al. 2022

J Exp Clin Cancer Res

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Background Anaplastic Thyroid Cancer (ATC) is an undifferentiated and aggressive tumor that often originates from well-Differentiated Thyroid Carcinoma (DTC) through a trans-differentiation process. Epithelial-to-Mesenchymal Transition (EMT) is recognized as one of the major players of this process. OVOL2 is a transcription factor (TF) that promotes epithelial differentiation and restrains EMT during embryonic development. OVOL2 loss in some types of cancers is linked to aggressiveness and poor prognosis. Here, we aim to clarify the unexplored role of OVOL2 in ATC. Methods Gene expression analysis in thyroid cancer patients and cell lines showed that OVOL2 is mainly associated with epithelial features and its expression is deeply impaired in ATC. To assess OVOL2 function, we established an OVOL2-overexpression model in ATC cell lines and evaluated its effects by analyzing gene expression, proliferation, invasion and migration abilities, cell cycle, specific protein localization through immunofluorescence staining. RNA-seq profiling showed that OVOL2 controls a complex network of genes converging on cell cycle and mitosis regulation and Chromatin Immunoprecipitation identified new OVOL2 target genes. Results Coherently with its reported function, OVOL2 re-expression restrained EMT and aggressiveness in ATC cells. Unexpectedly, we observed that it caused G2/M block, a consequent reduction in cell proliferation and an increase in cell death. This phenotype was associated to generalized abnormalities in the mitotic spindle structure and cytoskeletal organization. By RNA-seq experiments, we showed that many pathways related to cytoskeleton and migration, cell cycle and mitosis are profoundly affected by OVOL2 expression, in particular the RHO-GTPase pathway resulted as the most interesting. We demonstrated that RHO GTPase pathway is the central hub of OVOL2-mediated program in ATC and that OVOL2 transcriptionally inhibits RhoU and RhoJ. Silencing of RhoU recapitulated the OVOL2-driven phenotype pointing to this protein as a crucial target of OVOL2 in ATC. Conclusions Collectively, these data describe the role of OVOL2 in ATC and uncover a novel function of this TF in inhibiting the RHO GTPase pathway interlacing its effects on EMT, cytoskeleton dynamics and mitosis.

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Section: Discussionmentioning

confidence: 99%

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Gugnoni

Manzotti

Vitale

et al. 2022

J Exp Clin Cancer Res

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“…11 PARP1-induced PARylation was a key event in OVOL2-mediated regulation of chromosome integrity and inhibition of cancer cell growth. 27 OVOL2 expression was associated with MET in OS cells and inhibited ZEB1 expression and OS progression. 12 OVOL2 played a key role in inhibiting NPC metastasis and maintaining the epithelial phenotype.…”

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confidence: 92%

Comprehensive Analysis of the Expression, Prognosis, and Biological Significance of OVOLs in Breast Cancer

Chen¹,

Tang²,

Li³

et al. 2021

IJGM

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Background:The study aimed to investigate the expression of OVOLs in breast cancer (BRCA) tissues and their value in prognosis. Methods: ONCOMINE was used to analyze the expressions of OVOL1, OVOL2, and OVOL3 mRNA between BRCA tissues and normal breast tissues. The Wilcoxon rank sum test and t-test were used to assess the expression of OVOLs between BRCA tissues and unpaired/paired normal breast tissues. GEPIA and ROC curves were used to analyze the relationship between OVOLs expression and clinical pathological stage. Kaplan-Meier plotter was used to analyze prognosis. cBioPortal was used to analyze the mutation of OVOLs. GEPIA was used to analyze the co-expression of OVOLs. GO and KEGG analyses were performed by the DAVID software to predict the function of OVOLs co-expression genes. Results: The expression of OVOL1/2 was significantly higher in BRCA tissues than in normal breast tissues. The OVOL3 expression correlated with tumor stage. The AUC of OVOLs was 0.757, 0.754, and 0.537, respectively. OVOL1 high expression was associated with shorter overall survival (HR: 1.48; 95% CI: 1.07-2.04; P=0.018). The OVOLs were associated with pathways including axon guidance, thyroid hormone signaling pathway, and ubiquinone and other terpenoid-quinone biosynthesis. Conclusion: OVOL1 is a new potential marker of prognosis in BRCA, and OVOL1/2 are potential therapeutic targets in BRCA.

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“…OVO-like zinc finger 2 (OVOL2), a member of the OVO family of conserved zinc-finger transcription factors, can regulate embryonic development and cancer metastasis. [11][12][13][14][15][16][17] It has been reported that Ovol2 gene knockout (KO) in mice results in embryonic lethality before embryonic day 10.5, indicating that OVOL2 is involved in early embryonic development. [11] OVOL2 expression was shown to be downregulated in hepatocellular carcinoma and colorectal cancer.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Repression of Aerobic Glycolysis by OVOL2 in Breast Cancer

Zhang

Luo

et al. 2022

Advanced Science

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Aerobic glycolysis (Warburg effect), a hallmark of cancer, plays a critical role in cancer cell growth and metastasis; however, direct inhibition of the Warburg effect remains largely unknown. Herein, the transcription factor OVO-like zinc finger 2 (OVOL2) is demonstrated to directly repress the expression of several glycolytic genes, blocking the Warburg effect and breast tumor growth and metastasis in vitro and in vivo. OVOL2 inhibits glycolysis by recruiting the nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3). The tumor suppressor p53, a key regulator of cancer metabolism, activates OVOL2 by binding to the oncoprotein mouse double minute 2 homolog (MDM2) and inhibiting MDM2-mediated ubiquitination and degradation of OVOL2. OVOL2 expression is negatively correlated with glycolytic gene expression and can be a good predictor of prognosis in patients with breast cancer. Therefore, targeting the p53/MDM2/OVOL2 axis provides a potential avenue for cancer treatment, especially breast cancer.

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Poly(ADP-ribosyl)ation of OVOL2 regulates aneuploidy and cell death in cancer cells

Cited by 8 publications

References 49 publications

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

OVOL2 impairs RHO GTPase signaling to restrain mitosis and aggressiveness of Anaplastic Thyroid Cancer

Comprehensive Analysis of the Expression, Prognosis, and Biological Significance of OVOLs in Breast Cancer

Transcriptional Repression of Aerobic Glycolysis by OVOL2 in Breast Cancer

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