The pseudogene PTENP1 regulates smooth muscle cells as a competing endogenous RNA

Abstract

The long non-coding RNA (lncRNA) PTENP1 is a pseudogene of phosphatase and tensin homologue deleted on chromosome ten (PTEN), has been implicated in smooth muscle cell (SMC) proliferation and apoptosis. PTENP1 is the pseudogene of PTEN. However, it is unclear whether and how PTENP1 functions in the proliferation and apoptosis of human aortic SMCs (HASMCs). Here, we hypothesised that PTENP1 inhibits HASMC proliferation and enhances apoptosis by promoting PTEN expression. PCR analysis and Western blot assays respectively showed that both PTENP1 and PTEN were up-regulated in human aortic dissection (AD) samples. PTENP1 overexpression significantly increased the protein expression of PTEN, promoted apoptosis and inhibited the proliferation of HASMCs. PTENP1 silencing exhibited the opposite effects and mitigated H2O2-induced apoptosis of HASMCs. In an angiotensin II (Ang II)-induced mouse aortic aneurysm (AA) model, PTENP1 overexpression potentiated aortic SMC apoptosis, exacerbated aneurysm formation. Mechanistically, RNA pull-down assay and a series of luciferase reporter assays using miR-21 mimics or inhibitors identified PTENP1 as a molecular sponge for miR-21 to endogenously compete for the binding between miR-21 and the PTEN transcript, releasing PTEN expression. This finding was further supported by in vitro immunofluorescent evidence showing decreased cell apoptosis upon miR-21 mimic administration under baseline PTENP1 overexpression. Ex vivo rescue of PTEN significantly mitigated the SMC apoptosis induced by PTENP1 overexpression. Finally, Western blot assays showed substantially reduced Akt phosphorylation and cyclin D1 and cyclin E levels with up-regulated PTENP1 in HASMCs. Our study identified PTENP1 as a mediator of HASMC homeostasis and suggests that PTENP1 is a potential target in AD or AA intervention.

Pseudogene-Derived lncRNAs and Their miRNA Sponging Mechanism in Human Cancer

“…However, compared with other members of lncRNAs, transcribed pseudogenes-derived lncRNAs have not been paid attention previously. Recent studies have demonstrated that transcribed pseudogenederived lncRNAs play important roles in multiple biological processes, such as cell proliferation, cell cycle, cell migration and cell death (Lai et al, 2019;Oliveira-Mateos et al, 2019;Varesio et al, 2019).…”

Quality Control Strategy for CRISPR-Cas9-Based Gene Editing Complicated by a Pseudogene

“…Nevertheless, the risks and consequences of an alteration of the pseudogenes were underrated. For example, PTEN, a gene implicated in cancer, has been edited by several teams (Wang et al, 2015;Hill et al, 2017), without final sequencing of its pseudogene PTENP1 even though PTENP1 is acting as a ceRNA of PTEN (Lai et al, 2019). Kawamura and colleagues were confronted with issues related to pseudogene homology when undertaking the CRISPR-Cas9 KO of NANOG which has 10 pseudogenes (Kawamura et al, 2015).…”

Not So Dead Genes—Retrocopies as Regulators of Their Disease-Related Progenitors and Hosts

“…PTENP1 and its parental gene, PTEN , were found to be upregulated in human aortic dissection samples. In this case PTENP1 also works as a microRNA sponge competing for miR-21 with parental gene transcripts, and overexpression of lncRNA results in elevated level of PTEN protein [ 81 ].…”