Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis

Hanniford, Douglas; Ulloa-Morales, Alejandro; Karz, Alcida; Berzoti-Coelho, Maria Gabriela; Moubarak, Rana S.; Sánchez‐Sendra, Beatriz; Kloetgen, Andreas; Dávalos, Verónica; Imig, Jochen; Wu, Pamela; Vasudevaraja, Varshini; Argibay, Diana; Lilja, Karin; Tabaglio, Tommaso; Monteagudo, Carlos; Guccione, Ernesto; Tsirigos, Aristotelis; Osman, Iman; Aifantis, Iannis; Hernando, Eva

doi:10.1016/j.ccell.2019.12.007

Cited by 233 publications

(198 citation statements)

References 107 publications

(123 reference statements)

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“…However, we should acknowledge the limitations of this work: 1) the lack of in vivo animal model results to strengthen the importance of HAND2-AS1/miR-590-3p/ KCNT2 triplets in GC development; and 2) we did not investigate the upstream mechanism that is responsible for the elevated expression status of HAND2-AS1 in GC. There are studies showed epigenetic modifications can affect lncRNA expression in cancers, 22,23 which may be a mechanism for the decreased expression of HAND2-AS1 and deserves to be deeply investigated in the future.…”

Section: Hand2-as1 Regulates Gc Cell Behaviors Via Regulating Mir-590mentioning

confidence: 99%

<p>Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis</p>

Yu¹,

Li²,

Li³

et al. 2020

OTT

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Introduction: Long non-coding RNAs (lncRNAs) are regarded as crucial regulators for cancer initiation and progression. Heart and Neural Crest Derivatives Expressed 2 antisense RNA 1 (HAND2-AS1) was recently proposed to function as tumor suppressor in several human cancers. However, its role in gastric cancer (GC) remains unclear. Methods: HAND2-AS1 expression in GC tissues and normal tissues was analyzed at GEPIA (a web server for gene expression profiling analysis). Moreover, RT-qPCR method was utilized to explore HAND2-AS1 expression in GC cells and normal cell. In vitro experiments were carried out using cell counting kit-8 assay, colony formation assay, and flow cytometry assay, respectively. Bioinformatic analysis and luciferase activity reporter assay were performed to identify the downstream targets of HAND2-AS1. Results: We found HAND2-AS1 has decreased expression in both GC tissues and cells. Overexpression of HAND2-AS1 was able to inhibit GC cell proliferation, colony formation, but promote apoptosis. On the contrary, knockdown of HAND2-AS1 could cause the opposite effects on GC cells. Furthermore, HAND2-AS1 was shown to function as a competitive RNA that binds with microRNA-590-3p (miR-590-3p) to affect the expression of potassium sodium-activated channel subfamily T member 2 (KCNT2). Discussion: Our results indicated the tumor suppressive role of HAND2-AS1 in GC. Also, the newly identified HAND2-AS1/miR-590-3p/KCNT2 axis will help us to understand the role of HAND2-AS1 in cancer.

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Section: Hand2-as1 Regulates Gc Cell Behaviors Via Regulating Mir-590mentioning

confidence: 99%

<p>Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis</p>

Yu¹,

Li²,

Li³

et al. 2020

OTT

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“…We look forward to seeing in future studies whether the ndings of this paper apply to other tumors, such as ovarian cancer or even to other diseases. Previous reports revealed that a certain circRNA formed by cyclization of lncRNA may have different functions and mechanisms in different biological process, such as the CDR1as [21,48,49]. Thus, future iterations of comprehensive understanding of circCDKN2B-AS1 biogenesis, binding proteins/microRNAs, effects on aerobic glycolysis and tumorigenesis programs may in fact demonstrate even greater potency.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of circRNAs on the development in various cancers has been reported, such as breast cancer, oral cancer and hepatocellular carcinoma [14][15][16], Most of the discoveries revealed that circRNAs can function by sponging microRNAs and regulating the expression level of target genes [17][18]. Recent studies revealed that circRNAs can bind with RNA binding proteins (RBPs) [19][20][21], however, the potential value of circRNAs-RBP complex is still elusive and the biological function of most circRNAs in clinic is still unkonwn.…”

Section: Introductionmentioning

confidence: 99%

CircCDKN2B-AS1 Interacts with IMP3 to Stabilize Hexokinase 2 mRNA and Facilitate Cervical Squamous Cell Carcinoma Aerobic Glycolysis Progression

Zhang

Zhao

Yang

et al. 2020

Preprint

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Background: Circular RNAs(circRNAs) have been reported to play key roles in the development of various cancers. However, the biological function and clinical significance of most circRNAs are still elusive. The purpose of this study is to explore the function and mechanism of a certain circRNA named circCDKN2B-AS1 in cervical cancer development, and its potential value in clinic. Methods: The qRT-PCR array was conducted to verify the expression level of circCDKN2B-AS1. CCK8 assay, transwell assay, and FCM were undertaken to detect cellular proliferation, migration, and apoptosis, respectively. Seahorse XFe 96 analyzer was used to measure the glycolysis metabolism level. RNA pulldown, RIP, actinomycin-D adding assay and Western Blot were used to screen and elucidate the potential mechanisms. BALB/c nude mice and zebrafish embryo（AB,WT） were used as animal models to investigate tumorigenesis capability.18FDG-microPET/CT was used to detect the glucose metabolism level of subcutaneous tumor in nude mice. Results: CircCDKN2B-AS1, circular isoform of lncRNA CDKN2B-AS1, was upregulated in cervical cancer and precancer tissues. We found that circCDKN2B-AS1 associated with IMP3 protein depending on a specific binding site and regulated the stability of Hexokinase 2(HK2) mRNA, the rate-limiting enzyme of aerobic glycolysis pathway. The expression level of circCDKN2B-AS1 fated the binding of IMP3 to 3’UTR of HK2 mRNA, consequently affects cell malignant phenotypes and aerobic glycolysis of cervical cancer in vitro and in vivo. Mutant circCDKN2B-AS1 lacking of the IMP3 binding site didn’t have such effects. Utilizing an inhibitory peptide to block the interaction between circCDKN2B-AS1 and IMP3 protein impeded the binding of IMP3 to 3’UTR of HK2 mRNA and suppressed aerobic glycolysis in cervical cancer cells.Conclusions: Our findings demonstrate that circCDKN2B-AS1 facilitates aerobic glycolysis by sponging IMP3 protein to stabilize HK2 mRNA, consequently promotes malignant phenotypes in cervical cancer, which may provide a potential approach for cervical cancer therapeutics.

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“…This suggests that glutathione can be a metabolic link between drug-induced dedifferentiation and sensitivity to ferroptosis-inducing agents, and this was confirmed by supplementation of the culture medium with GSH that rescued melanoma from ferroptosis [193]. Recently, cerebellar degeneration-related 1 antisense (CDR1as) has been identified as a novel marker of melanoma cell differentiation state, and depletion of CDR1as was associated with the metastatic potential of melanoma [197]. It has been found that CDR1as high cells were substantially more sensitive to inhibitors of GPX4, thus induction of ferroptosis.…”

Section: Ferroptosis In Melanomamentioning

confidence: 91%

“…It has been found that CDR1as high cells were substantially more sensitive to inhibitors of GPX4, thus induction of ferroptosis. In addition, high levels of CDR1as have been preferentially associated with melanoma cell state marked by low MITF level and high AXL level [197]. Thus, expression of CDR1as may serve as a determinant of phenotypic state of melanoma cells that may be targeted by inducers of ferroptosis.…”

Section: Ferroptosis In Melanomamentioning

confidence: 99%

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

Hartman

2020

IJMS

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Resisting cell death is a hallmark of cancer. Disturbances in the execution of cell death programs promote carcinogenesis and survival of cancer cells under unfavorable conditions, including exposition to anti-cancer therapies. Specific modalities of regulated cell death (RCD) have been classified based on different criteria, including morphological features, biochemical alterations and immunological consequences. Although melanoma cells are broadly equipped with the anti-apoptotic machinery and recurrent genetic alterations in the components of the RAS/RAF/MEK/ERK signaling markedly contribute to the pro-survival phenotype of melanoma, the roles of autophagy-dependent cell death, necroptosis, ferroptosis, pyroptosis, and parthanatos have recently gained great interest. These signaling cascades are involved in melanoma cell response and resistance to the therapeutics used in the clinic, including inhibitors of BRAF mut and MEK1/2, and immunotherapy. In addition, the relationships between sensitivity to non-apoptotic cell death routes and specific cell phenotypes have been demonstrated, suggesting that plasticity of melanoma cells can be exploited to modulate response of these cells to different cell death stimuli. In this review, the current knowledge on the non-apoptotic cell death signaling pathways in melanoma cell biology and response to anti-cancer drugs has been discussed.

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Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis

Cited by 233 publications

References 107 publications

<p>Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis</p>

<p>Long Non-Coding RNA HAND2-AS1 Inhibits Growth and Migration of Gastric Cancer Cells Through Regulating the miR-590-3p/KCNT2 Axis</p>

CircCDKN2B-AS1 Interacts with IMP3 to Stabilize Hexokinase 2 mRNA and Facilitate Cervical Squamous Cell Carcinoma Aerobic Glycolysis Progression

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

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