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

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2020 Jan 15

PMID 31935372

Citations 170

Authors

Douglas Hanniford

Alejandro Ulloa-Morales

Alcida Karz

Maria Gabriela Berzoti-Coelho

Rana S Moubarak

Beatriz Sanchez-Sendra

Andreas Kloetgen

Veronica Davalos

Jochen Imig

Pamela Wu

Varshini Vasudevaraja

Diana Argibay

Karin Lilja

Tommaso Tabaglio

Carlos Monteagudo

Ernesto Guccione

Aristotelis Tsirigos

Iman Osman

Iannis Aifantis

Eva Hernando

Affiliations

Soon will be listed here.

Abstract

Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels reflect cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic, and predictive roles for CDR1as and expose circRNAs as key players in metastasis.

Citing Articles

The prognosis of ciRS-7 and circHIPK3 in pan-cancer: a mini-review and meta-analysis.

Li X, Wu T, Dong R, Wu X Discov Oncol. 2025; 16(1):207.

PMID: 39969753 PMC: 11839969. DOI: 10.1007/s12672-025-01944-2.

Circular RNAs in neurological conditions - computational identification, functional validation, and potential clinical applications.

Hatzimanolis O, Sykes A, Cristino A Mol Psychiatry. 2025; .

PMID: 39966624 DOI: 10.1038/s41380-025-02925-1.

Circular RNA circAGAP1 promotes sunitinib sensitivity in renal cell carcinoma via sponging multiple PDGFR-targeted miRNAs.

Lv Q, Wang G, Hong Y, Zhu T, Qin S, Sun S Oncol Res. 2025; 33(2):407-420.

PMID: 39866227 PMC: 11754003. DOI: 10.32604/or.2024.047698.

hnRNPU-mediated pathogenic alternative splicing drives gastric cancer progression.

Jin G, Song Y, Fang S, Yan M, Yang Z, Shao Y J Exp Clin Cancer Res. 2025; 44(1):8.

PMID: 39773744 PMC: 11705778. DOI: 10.1186/s13046-024-03264-9.

The Role of Non-coding RNAs in Tumorigenesis, Diagnosis/Prognosis, and Therapeutic Strategies for Cutaneous Melanoma.

Schaft N, Dorrie J Methods Mol Biol. 2024; 2883:79-107.

PMID: 39702705 DOI: 10.1007/978-1-0716-4290-0_4.

References

Hu B, Yang Y, Huang Y, Zhu Y, Lu Z . POSTAR: a platform for exploring post-transcriptional regulation coordinated by RNA-binding proteins. Nucleic Acids Res. 2017; 45(D1):D104-D114. PMC: 5210617. DOI: 10.1093/nar/gkw888. View

Konieczkowski D, Johannessen C, Abudayyeh O, Kim J, Cooper Z, Piris A . A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 2014; 4(7):816-27. PMC: 4154497. DOI: 10.1158/2159-8290.CD-13-0424. View

Schneider T, Hung L, Schreiner S, Starke S, Eckhof H, Rossbach O . CircRNA-protein complexes: IMP3 protein component defines subfamily of circRNPs. Sci Rep. 2016; 6:31313. PMC: 4980667. DOI: 10.1038/srep31313. View

Yang W, Sriramaratnam R, Welsch M, Shimada K, Skouta R, Viswanathan V . Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014; 156(1-2):317-331. PMC: 4076414. DOI: 10.1016/j.cell.2013.12.010. View

Jonson L, Christiansen J, Hansen T, Vikesa J, Yamamoto Y, Nielsen F . IMP3 RNP safe houses prevent miRNA-directed HMGA2 mRNA decay in cancer and development. Cell Rep. 2014; 7(2):539-551. DOI: 10.1016/j.celrep.2014.03.015. View

Holdt L, Stahringer A, Sass K, Pichler G, Kulak N, Wilfert W . Circular non-coding RNA ANRIL modulates ribosomal RNA maturation and atherosclerosis in humans. Nat Commun. 2016; 7:12429. PMC: 4992165. DOI: 10.1038/ncomms12429. View

Dixon S, Lemberg K, Lamprecht M, Skouta R, Zaitsev E, Gleason C . Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012; 149(5):1060-72. PMC: 3367386. DOI: 10.1016/j.cell.2012.03.042. View

Kong X, Li G, Yuan Y, He Y, Wu X, Zhang W . MicroRNA-7 inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via targeting FAK expression. PLoS One. 2012; 7(8):e41523. PMC: 3410899. DOI: 10.1371/journal.pone.0041523. View

Souroullas G, Jeck W, Parker J, Simon J, Liu J, Paulk J . An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation. Nat Med. 2016; 22(6):632-40. PMC: 4899144. DOI: 10.1038/nm.4092. View

10.

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

11.

Lederer M, Bley N, Schleifer C, Huttelmaier S . The role of the oncofetal IGF2 mRNA-binding protein 3 (IGF2BP3) in cancer. Semin Cancer Biol. 2014; 29:3-12. DOI: 10.1016/j.semcancer.2014.07.006. View

12.

Kaufman C, Mosimann C, Fan Z, Yang S, Thomas A, Ablain J . A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation. Science. 2016; 351(6272):aad2197. PMC: 4868069. DOI: 10.1126/science.aad2197. View

13.

Vikesaa J, Hansen T, Jonson L, Borup R, Wewer U, Christiansen J . RNA-binding IMPs promote cell adhesion and invadopodia formation. EMBO J. 2006; 25(7):1456-68. PMC: 1440323. DOI: 10.1038/sj.emboj.7601039. View

14.

Huang C, Liang D, Tatomer D, Wilusz J . A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs. Genes Dev. 2018; 32(9-10):639-644. PMC: 6004072. DOI: 10.1101/gad.314856.118. View

15.

Van Nostrand E, Freese P, Pratt G, Wang X, Wei X, Xiao R . A large-scale binding and functional map of human RNA-binding proteins. Nature. 2020; 583(7818):711-719. PMC: 7410833. DOI: 10.1038/s41586-020-2077-3. View

16.

Ashwal-Fluss R, Meyer M, Pamudurti N, Ivanov A, Bartok O, Hanan M . circRNA biogenesis competes with pre-mRNA splicing. Mol Cell. 2014; 56(1):55-66. DOI: 10.1016/j.molcel.2014.08.019. View

17.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

18.

Piwecka M, Glazar P, Hernandez-Miranda L, Memczak S, Wolf S, Rybak-Wolf A . Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science. 2017; 357(6357). DOI: 10.1126/science.aam8526. View

19.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin A, Kim S . The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012; 483(7391):603-7. PMC: 3320027. DOI: 10.1038/nature11003. View

20.

Lambert A, Pattabiraman D, Weinberg R . Emerging Biological Principles of Metastasis. Cell. 2017; 168(4):670-691. PMC: 5308465. DOI: 10.1016/j.cell.2016.11.037. View