Block one, unleash a hundred. Mechanisms of DAB2IP inactivation in cancer

Abstract

One of the most defining features of cancer is aberrant cell communication; therefore, a molecular understanding of the intricate network established among tumor cells and their microenvironment could significantly improve comprehension and clinical management of cancer. The tumor suppressor DAB2IP (Disabled homolog 2 interacting protein), also known as AIP1 (ASK1 interacting protein), has an important role in this context, as it modulates signal transduction by multiple inflammatory cytokines and growth factors. DAB2IP is a Ras-GAP, and negatively controls Ras-dependent mitogenic signals. In addition, acting as a signaling adaptor, DAB2IP modulates other key oncogenic pathways, including TNFα/NF-κB, WNT/β-catenin, PI3K/AKT, and androgen receptors. Therefore, DAB2IP inactivation can provide a selective advantage to tumors initiated by a variety of driver mutations. In line with this role, DAB2IP expression is frequently impaired by methylation in cancer. Interestingly, recent studies reveal that tumor cells can employ other sophisticated mechanisms to disable DAB2IP at the post-transcriptional level. We review the mechanisms and consequences of DAB2IP inactivation in cancer, with the purpose to support and improve research aimed to counteract such mechanisms. We suggest that DAB2IP reactivation in cancer cells could be a strategy to coordinately dampen multiple oncogenic pathways, potentially limiting progression of a wide spectrum of tumors.

Cell-autonomous and cell non-autonomous downregulation of tumor suppressor DAB2IP by microRNA-149-3p promotes aggressiveness of cancer cells

“…h Proposed model for miR-149-3p-mediated cell autonomous and cell non-autonomous inhibition of DAB2IP transcriptional program of prostate cancer cells silenced for DAB2IP. As expected, upon DAB2IP knockdown, we observed upregulation of genes involved in biological processes and pathways modulated by DAB2IP, such as NF-kB activation by TNF, unfolded protein response (UPR), EMT, apoptosis, K-Ras, p38MAP kinase, and STAT signaling [4,5]. In addition, we detected enrichment for genes implicated in hypoxia, inflammation, and immune system regulation, suggesting a role for DAB2IP in additional molecular circuits.…”

“…The tumor suppressor DAB2IP is an important modulator of multiple oncogenic signaling pathways, and is disabled in malignancies through multiple mechanisms [5]. Using highthroughput functional screening, we identified novel miR-NAs able to target DAB2IP.…”

“…Through an interaction with signaling modulators and potential oncogenes, DAB2IP controls multiple pathways, including Ras/MAPK [1], apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK)/p38 MAPK [2], NF-κB [1], and phosphoinositide 3-kinase (PI3K)/AKT signaling [3], affecting cell behavior in response to a variety of extrinsic inputs. The loss-of-function of this modulator can therefore amplify the cancer cell's response to multiple oncogenic signals, fostering tumor progression [4,5]. A consistent body of literature reports epigenetic inactivation of DAB2IP by promoter methylation in malignant cells [6,7].…”

“…Recently, other molecular mechanisms of DAB2IP inactivation in cancer have been identified. Multiple E3 ubiquitin-ligases can promote its turnover, while AKT kinase-mediated phosphorylation counteracts DAB2IP functions [4,5]. In addition, cytoplasmic interaction with tumorassociated p53 mutants blocks DAB2IP inhibitory activity on NF-κB and on AKT, favoring respectively cancer cell dissemination in response to inflammatory stimuli [8], and insulin-induced proliferation and invasion of tumor cells [9].…”

Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP

“…In addition, DAB2IP modulates other crucial oncogenic pathways, and inhibits epithelialmesenchymal transition (EMT) in cancer cells (recently reviewed in refs. 17,18). Interestingly, DAB2IP is a negative modulator of PI3K/AKT signaling, because it binds PI3K-p85, limiting AKT activation in response to various stimuli (19).…”