Pseudogene-Mediated DNA Demethylation Leads to Oncogene Activation. (Sci Adv, Oct 2021)


Junsu Kwon 1Yanjing V Liu 1Chong Gao 2Mahmoud A Bassal 1 3Adrianna I Jones 3Junyu Yang 2Zhiyuan Chen 2Ying Li 1Henry Yang 1Leilei Chen 1Annalisa Di Ruscio 4 5 6Yvonne Tay 1 7Li Chai 2Daniel G Tenen 1 3 4


1Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.

2Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA.

3Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115 USA.

4Harvard Medical School Initiative for RNA Medicine, Harvard Medical School, Boston, MA 02115, USA.

5Department of Translational Medicine, University of Eastern Piedmont, Novara 28100, Italy.

6Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02214, USA.

7Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.


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.

PMID: 34597139

DOI: 10.1126/sciadv.abg1695