Research Papers:

The impact of the RASSF1C and PIWIL1 on DNA methylation: the identification of GMIP as a tumor suppressor

Yousef G. Amaar _ and Mark E. Reeves

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Oncotarget. 2020; 11:4082-4092. https://doi.org/10.18632/oncotarget.27795

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Yousef G. Amaar1 and Mark E. Reeves1,2

1 Surgical Oncology Laboratory, Loma Linda VA Medical Center, Loma Linda, CA, USA

2 Loma Linda University Cancer Center, Loma Linda, CA, USA

Correspondence to:

Yousef G. Amaar,email: [email protected]

Keywords: lung cancer; RASSF1C; PIWIL1; DNA metylation;

Received: May 11, 2020     Accepted: October 17, 2020     Published: November 10, 2020

Copyright: © 2020 Amaar and Reeves. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Introduction: Recently we have identified a novel RASSF1C-PIWIL1-piRNA pathway that promotes lung cancer cell progression and migration. PIWI-like proteins interact with piRNAs to form complexes that regulate gene expression at the transcriptional and translational levels. We have illustrated in previous work that RASSF1C modulates the expression of the PIWIL1-piRNA gene axis, suggesting the hypothesis that the RASSF1C-PIWI-piRNA pathway could potentially contribute to lung cancer stem cell development and progression, in part, through modulation of gene methylation of both oncogenic and tumor suppressor genes. Therefore, we tested this hypothesis using a non-small cell lung cancer (NSCLC) cell model to identify Candidate Differentially Methylated Regions (DMRs) modulated by the RASSF1C-PIWIL1-piRNA pathway.

Materials and Methods: We studied the impact of over-expressing RASSF1C and knocking down RASSF1C and PIWIL1 expression on global gene DNA methylation in the NSCLC cell line H1299 using the Reduced Representation Bisulfite Sequencing (RRBS) method.

Results: DMRs were identified by comparing DNA methylation profiles of experimental and control cells. Over-expression of RASSF1C and knocking down RASSF1C and PIWIL1 modulated DNA methylation of genomic regions; and statistically significant candidate genes residing DMR regions in lung cancer cells were identified, including oncogenes and tumor suppressors. One of the hypermethylated genes, Gem Interacting Protein (GMIP), displays tumor suppressor properties. GMIP expression attenuates lung cancer cell migration, and its over-expression is associated with longer survival of lung cancer patients.

Conclusions: The RASSF1C-PIWI-piRNA pathway modulates key oncogenes and tumor suppressor genes. GMIP is hypermethylated by this pathway and has tumor suppressor properties.

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