Journal
SCIENCE ADVANCES
Volume 7, Issue 40, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abg1695
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Funding
- Singapore Ministry of Health's National Medical Research Council
- NIH [1R35CA197697, P01HL131477]
- Singapore National Research Foundation Fellowship
- National University of Singapore President's Assistant Professorship
- National Research Foundation Singapore
- Singapore Ministry of Education
- RNA Biology Center at the Cancer Science Institute of Singapore, NUS under the Singapore Ministry of Education's AcRF Tier 3 grants [MOE2014-T3-1-006]
- NIH/NHLBI [P01HL095489]
- Xiu Research Fund
- NCI [R00CA188595]
- Italian Association for Cancer Research (AIRC) [2014-15347]
- Giovanni Armenise-Harvard Foundation
- FY19 Bone Marrow Failure Research Program Idea Development Award [W81XWH-19-BMFRPIDA]
- Department of Defense [W81XWH2010518]
- U.S. Department of Defense (DOD) [W81XWH2010518] Funding Source: U.S. Department of Defense (DOD)
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This study has identified a previously unrecognized role for pseudogenes as potent epigenetic regulators in hepatocellular carcinoma, where they can demethylate and activate oncogenes by interacting with DNMT1. This finding expands our understanding of pseudogenes beyond being considered nonfunctional evolutionary relics.
Pseudogenes, noncoding homologs of protein-coding genes, once considered nonfunctional evolutionary relics, have recently been linked to patient prognoses and cancer subtypes. Despite this potential clinical importance, only a handful of >12,000 pseudogenes in humans have been characterized in cancers to date. Here, we describe a previously unrecognized role for pseudogenes as potent epigenetic regulators that can demethylate and activate oncogenes. We focused on SALL4, a known oncogene in hepatocellular carcinoma (HCC) with eight pseudogenes. Using a locus-specific demethylating technology, we identified the critical CpG region for SALL4 expression. We demonstrated that SALL4 pseudogene 5 hypomethylates this region through interaction with DNMT1, resulting in SALL4 up-regulation. Intriguingly, pseudogene 5 is significantly up-regulated in a hepatitis B virus model before SALL4 induction, and both are increased in patients with HBV-HCC. Our results suggest that pseudogene-mediated demethylation represents a novel mechanism of oncogene activation in cancer.
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