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

Douglas Hanniford; Alejandro Ulloa-Morales; Alcida Karz; Maria Gabriela Berzoti-Coelho; Rana S Moubarak; Beatriz Sánchez-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

doi:10.1016/j.ccell.2019.12.007

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

Cancer Cell. 2020 Jan 13;37(1):55-70.e15. doi: 10.1016/j.ccell.2019.12.007.

Authors

Douglas Hanniford¹, Alejandro Ulloa-Morales², Alcida Karz², Maria Gabriela Berzoti-Coelho³, Rana S Moubarak², Beatriz Sánchez-Sendra⁴, Andreas Kloetgen², Veronica Davalos⁵, Jochen Imig², Pamela Wu⁶, Varshini Vasudevaraja⁷, Diana Argibay², Karin Lilja⁸, Tommaso Tabaglio⁹, Carlos Monteagudo¹⁰, Ernesto Guccione¹¹, Aristotelis Tsirigos¹², Iman Osman¹³, Iannis Aifantis², Eva Hernando¹⁴

Affiliations

¹ Department of Pathology, New York University Langone Medical Center, New York, NY, USA; Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA. Electronic address: [email protected].
² Department of Pathology, New York University Langone Medical Center, New York, NY, USA; Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA.
³ Department of Pathology, New York University Langone Medical Center, New York, NY, USA; Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
⁴ Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.
⁵ Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
⁶ Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA.
⁷ Applied Bioinformatics Laboratories, New York University Langone Medical Center, New York, NY, USA.
⁸ Department of Pathology, New York University Langone Medical Center, New York, NY, USA.
⁹ Institute of Molecular and Cell Biology, A(∗)STAR, Singapore, Singapore.
¹⁰ Department of Pathology, University of Valencia, Valencia, Spain.
¹¹ Institute of Molecular and Cell Biology, A(∗)STAR, Singapore, Singapore; Department of Oncological Sciences, Icahn School of Medicine, Mount Sinai, New York, NY, USA.
¹² Department of Pathology, New York University Langone Medical Center, New York, NY, USA; Applied Bioinformatics Laboratories, New York University Langone Medical Center, New York, NY, USA.
¹³ Departments of Urology and Medicine, New York University Langone Medical Center, New York, NY, USA; Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA.
¹⁴ Department of Pathology, New York University Langone Medical Center, New York, NY, USA; Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, NY, USA. Electronic address: [email protected].

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.

Keywords: CDR1as; EZH2; GPX4; IGF2BP; LINC00632; PRC2; circRNA; melanoma; metastasis; miR-7.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Autoantigens / genetics*
Enhancer of Zeste Homolog 2 Protein / genetics
Epigenesis, Genetic*
Gene Silencing*
Humans
Melanoma / pathology*
MicroRNAs / genetics
Neoplasm Invasiveness
Neoplasm Metastasis
Nerve Tissue Proteins / antagonists & inhibitors*
Nerve Tissue Proteins / genetics*
Phospholipid Hydroperoxide Glutathione Peroxidase / genetics
Prognosis
RNA, Antisense / genetics
RNA, Circular / genetics
RNA, Long Noncoding / genetics
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism*

Substances

Autoantigens
CDR1 protein, human
IGF2BP3 protein, human
MIRN7 microRNA, human
MicroRNAs
Nerve Tissue Proteins
RNA, Antisense
RNA, Circular
RNA, Long Noncoding
RNA-Binding Proteins
Phospholipid Hydroperoxide Glutathione Peroxidase
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding