Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis

Abstract

We previously discovered that systemic delivery of decorin for treatment of breast carcinoma xenografts induces paternally expressed gene 3 (Peg3), an imprinted gene encoding a zinc finger transcription factor postulated to function as a tumor suppressor. Here we found that de novo expression of Peg3 increased Beclin 1 promoter activity and protein expression. This process required the full-length Peg3 as truncated mutants lacking either the N-terminal SCAN domain or the zinc fingers failed to translocate to the nucleus and promote Beclin 1 transcription. Importantly, overexpression of Peg3 in endothelial cells stimulated autophagy and concurrently inhibited endothelial cell migration and evasion from a 3D matrix. Mechanistically, we found that Peg3 induced the secretion of the powerful angiostatic glycoprotein Thrombospondin 1 independently of Beclin 1 transcriptional induction. Thus, we provide a new mechanism whereby Peg3 can simultaneously evoke autophagy in endothelial cells and attenuate angiogenesis.

Decorin‐mediated oncosuppression – a potential future adjuvant therapy for human epithelial cancers

“…Both the core protein of decorin, especially the LRR domain, and the GAG side chain enable decorin to bind and sequester a large number of different molecules. These decorin‐interacting partners encompass versatile molecular categories including ECM macromolecules, growth factors and some of their receptors, cytokines, enzymes, hormones and lipoproteins (Figure ) (Yamaguchi et al, ; Bi and Yang, ; Gubbiotti et al, ; Torres et al, ). These interactions form the basis of decorin's multifaceted functions.…”

“…Regarding intestinal homeostasis, it was shown that decorin expression is vital for the maintenance of cell maturation (Bi et al, ). During tumourigenesis, decorin was further shown to be a regulator of the innate immune system (Merline et al, ; Frey et al, ), autophagy (Torres et al, ) and mitophagy (Buraschi et al, ), as discussed in more detail below. Although most of decorin's interactions are mediated via its core protein, the GAG side chain is also of great importance (Järvinen and Prince, ; Neill et al, ).…”

“…Decorin was also able to reprogramme the tumour stroma in a paracrine fashion, turning it into a less favourable environment for the progression of cancer (Buraschi et al, ). This effect has been linked with the evoked expression of paternally expressed gene 3 (Peg3), an imprinted tumour suppressor gene, which is directly involved in the regulation of endothelial cell autophagy (Torres et al, ). Also a more precise signalling cascade has been revealed in endothelial cells, where decorin, along with other molecules, inhibited anti‐autophagic signalling by suppressing Akt/mTOR/p706K activity, simultaneously activating AMPK‐mediated pro‐autophagic signalling pathways (Goyal et al, ).…”

“…Also a more precise signalling cascade has been revealed in endothelial cells, where decorin, along with other molecules, inhibited anti‐autophagic signalling by suppressing Akt/mTOR/p706K activity, simultaneously activating AMPK‐mediated pro‐autophagic signalling pathways (Goyal et al, ). Currently, decorin‐inducible Peg3 has been shown to attenuate angiogenesis via thrombospondin 1 expression, which occurs independently of signalling pathways leading to autophagy (Torres et al, ). In addition to acting as an endogenous inhibitor of angiogenesis, thrombospondin 1 is known to variously affect the behaviour of cancer cells including their proliferation, invasion and apoptosis (Torres et al, ).…”

“…Currently, decorin‐inducible Peg3 has been shown to attenuate angiogenesis via thrombospondin 1 expression, which occurs independently of signalling pathways leading to autophagy (Torres et al, ). In addition to acting as an endogenous inhibitor of angiogenesis, thrombospondin 1 is known to variously affect the behaviour of cancer cells including their proliferation, invasion and apoptosis (Torres et al, ).…”