The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells

Abstract

The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.

PTENp1, a natural sponge of miR‐21, mediates PTEN expression to inhibit the proliferation of oral squamous cell carcinoma

“…These results further confirmed the tumor‐suppressive role of PTENp1 . These findings were in line with previous studies involving lung cancer . Furthermore, PTENp1 overexpression could rescue the growth promoting, colony formation, cell‐cycle acceleration, and growth of xenografts by virtue of miR‐21.…”

Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis

“…HAUSP (also known as USP7) specifically removes the monoubiquitylation of PTEN and induces its nuclear export but has minimal effect on PTEN protein stability 22 . The Josephinfamily ataxin-3 regulates PTEN transcript abundance but not the protein stability 23 . A recent study, through a screen of 30 USP members, identified USP13 as a candidate that de-polyubiquitylates and stabilizes PTEN (ref.…”

Toward therapeutic targets for SCA3: Insight into the role of Machado–Joseph disease protein ataxin-3 in misfolded proteins clearance

“…The regulation of the basal level of chaperones may underlie the transcription factor activity of ataxin-3. As previously reported, ataxin-3 could function as a transcription factor to promote or inhibit target gene expression (Araujo et al, 2011;Evert et al, 2006;Li et al, 2002;Sacco et al, 2013). Therefore, down-regulation of chaperone expression may be due to a deficiency in transcriptional activation in mutant ataxin-3, though reports have suggested a similar activity of pathogenic ataxin-3 with 80Q and WT ataxin-3 toward modulation of expression from the hsp70 promoter (Reina et al, 2012).…”