Research Discovers That A Type Of Circular RNA Known As CDR1as Limits Skin Cancer Spread
A new study has found that a mysterious piece of genetic material restrains the spread of skin cancer
cells, but is frequently lost as they mature. Published online in Cancer Cell
, the new work revolves around circular RNA
, a recently described type of ribonucleic acid
Often, DNA blueprints are converted into RNA
and then into proteins with cellular functions. While most RNA
are linear molecules, some form circles
when their ends loop around and attach. Instead of encoding proteins, circular RNA
) seem to be part of complex regulatory systems, but their functions are still unclear, say the study authors.
The research led by researchers at New York University Grossman School of Medicine, which focuses only cell cultures and mice, is the first to show that a circRNA
blocks the aggressive spread of melanoma skin cancers
, and that its loss promotes it. A study analysis of human melanoma
tissues also linked higher CDR1as
levels with increased survival.
Often in patients that die from melanoma
, the most lethal form of skin cancer
, the aggressive spread, or metastasis, of cancer
cells is the primary cause of death. Cancer
cells arise from normal cells because of genetic errors, but changes in DNA do not fully explain how the cells spread.
Senior study author Eva Hernando, Ph.D., Associate Professor in the Department of Pathology at NYU Langone Health told Thailand Medical
News,"Our study provides new insights into the aggressive behavior of melanoma
, and is the first to expose a circRNA
as a suppressor of metastasis. We found CDR1as
restrains a known pro-cancer
protein called IGF2BP3, revealing a new function of CDR1as
that may have therapeutic implications."
Past research had suggested previously unknown functions for circRNAs
, including their binding with proteins that attach to RNA
to influence cell functions. Specifically, the new study reveals that metastasis of melanomas
proceeds when the interaction between CDR1as
and the RNA
-binding protein IGF2BP3 is disrupted.
The researchers say that if CDR1as
is active, IGF2BP3 proteins bind to its circular RNA
molecules, instead of attaching to other RNA
s that code for pro-metastatic proteins. When CDR1as
was removed using molecular techniques, IGF2BP3 was free to promote cancer
cell invasion, which occurs when cells penetrate skin
layers and spread to distant organs.
The research identifies the source of CDR1as
in cells as LINC00632, an example of yet another class of RNA
called long non-coding RNA
. Experiments revealed further that an "epigenetic" mechanism in melanoma cells silences the LINC00632 gene, which halts CDR1as
The researchers also say that epigenetic changes adjust the operation of genes without changing their DNA code, These include the attachment of molecules called methyl groups to histones, the "spools" around which DNA chains are wrapped. Methylation status determines whether a given stretch of DNA is unwound and accessible; or instead compacted, with the genes residing there silenced, researchers say.
The research found that a particular histone methylation, H3K27me3, silences the gene for LINC00632 in melanoma
cells starting to spread, which come to lack CDR1as
. The authors say that this interaction could represent a mechanism that helps cells migrate during normal (fetal) development, but that then drives cancer
spread when it mistakenly re-occurs in tumors.
Reference: Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis, Douglas Hanniford, Alejandro Ulloa-Morales, Alcida Karz, Iman Osman, Iannis Aifantis, Eva Hernando, Cancer Cell,