PIWI-like protein, HIWI2 is aberrantly expressed in retinoblastoma cells and affects cell-cycle potentially through OTX2

Abstract

Retinoblastoma (RB), a childhood cancer, is caused by biallelic mutation of the RB1 gene, but its development is not clearly understood. Furthermore, the presence of a cancer stem cell subpopulation in RB might impact its treatment. PIWI protein, known for its role in stem cell self-renewal, is aberrantly expressed in cancers. We examined the role of the PIWI-like protein HIWI2 in RB and its effect on the stem cell markers in cells of the RB line, Y79. The expression of HIWI2 is significantly increased in Y79 compared with its level in HeLa and ARPE19 cells. The stem cell markers Oct-3/4, Nanog and Sox-2 were not altered upon HIWI2 knockdown in Y79 cells. Interestingly, OTX2 was significantly downregulated in the absence of HIWI2. Otx2 transcripts also decreased in HIWI2-silenced Y79 and ARPE19 cells. Moreover, silencing HIWI2 in Y79 accumulated the cells at G2–M phase and reduced the levels of proliferating cell nuclear antigen (PCNA) and the tumor suppressor, p16. Our results demonstrate that HIWI2 is aberrantly expressed in Y79 cells and silencing of HIWI2 downregulates OTX2, suggesting that HIWI2 might play a role in the progression of RB.

Genome-wide by environment interaction studies of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

“…PIWIL4 is brain expressed and involved in chromatin modification 84 , suggesting it may moderate the effects of stress on depression. It encodes HIWI2, a protein thought to regulate OTX2, that is critical for the development of forebrain and for coordinating critical periods of plasticity disrupting the integration of cortical circuits 85,86 . Indeed, an intronic SNP in PIWIL4 was identified as the strongest GxE signal in attention deficit hyperactivity disorder using mother’s warmth as environmental exposure 87 .…”

Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland

“…PIWIL4 is brain-expressed and involved in chromatin-modification 85 , suggesting it may moderate the effects of stress on depression. It encodes HIWI2, a protein thought to regulate OTX2, which is critical for the development of forebrain and for coordinating critical periods of plasticity disrupting the integration of cortical circuits 86,87 . Indeed, an intronic SNP in PIWIL4 was identified as the strongest GxE signal in ADHD using mother’s warmth as environmental exposure 88 .…”

Editorial focus: understanding off-target effects as the key to successful RNAi therapy

“…Hence, piRNA safeguard mammalian germ cells from deleterious effects of transposons and preserve chromatin structure [79]. piRNAs guided silencing is analogous to the other RNAi mechanism in that piRNAs guide PIWI proteins to target mRNAs through RNA base pairing and the mRNAs are then dissected by the endonuclease activity of the PIWI proteins [80–83]. Although initial studies assigned piRNAs activity with mammalian germ cells, emerging evidence suggests that they may be functional in somatic cells as well [79, 81, 82, 84–91].…”