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.


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*


  • 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