Sirtuins and Hypoxia in EMT Control

Abstract

Epithelial-mesenchymal transition (EMT), a physiological process during embryogenesis, can become pathological in the presence of different driving forces. Reduced oxygen tension or hypoxia is one of these forces, triggering a large number of molecular pathways with aberrant EMT induction, resulting in cancer and fibrosis onset. Both hypoxia-induced factors, HIF-1α and HIF-2α, act as master transcription factors implicated in EMT. On the other hand, hypoxia-dependent HIF-independent EMT has also been described. Recently, a new class of seven proteins with deacylase activity, called sirtuins, have been implicated in the control of both hypoxia responses, HIF-1α and HIF-2α activation, as well as EMT induction. Intriguingly, different sirtuins have different effects on hypoxia and EMT, acting as either activators or inhibitors, depending on the tissue and cell type. Interestingly, sirtuins and HIF can be activated or inhibited with natural or synthetic molecules. Moreover, recent studies have shown that these natural or synthetic molecules can be better conveyed using nanoparticles, representing a valid strategy for EMT modulation. The following review, by detailing the aspects listed above, summarizes the interplay between hypoxia, sirtuins, and EMT, as well as the possible strategies to modulate them by using a nanoparticle-based approach.

Keywords: HIF; epithelial–mesenchymal transition; fibrosis; hypoxia; nanoparticles; sirtuins.

Figure 1

Schematic representation of the different actors and pathways leading to EMT induction.

Figure 2

Schematic illustration of the types of EMT. EMT can be differentiated into three types, based on the biological process with which it is associated. Type 1 is mostly associated with development and is characterized by markers such as PKC, ZO-1, etc. [7,36,37,38]. Type 2 is associated with the inflammatory-reparative process, including wound healing, and mostly involves cytoskeletal markers, such as Cytokeratins [39,40]. Type 3 is a gradual process associated with the acquisition of mesenchymal traits in epithelial cells and is mostly involved in cancer development. Its markers are Fibronectin, Vimentin, etc. [41,42,43,44].

Figure 3

Schematic illustration of different inductors of fibrosis in different organs. For each organ, we have indicated the sirtuins with a known protective effect.

Figure 4

Regulation of EMT by hypoxia through the induction of HIF-1, EPAS-1 (HIF-2), and HIF-3 transcription factors (HIF-dependent EMT induction). HIF-1 and HIF-2 directly regulate transcription factors directly or indirectly involved in EMT. On the other hand, the little that is known about HIF-3 suggests control over HIF-1α and HIF-2α more than a direct effect on EMT-transcription factors.

Figure 5

Regulation of EMT-related actors by hypoxia in a HIF-independent way. Transcription factors (NF-kB), growth factors (TGFβ), membrane receptors (Notch), and miRNAs can be modulated during hypoxia to control EMT.

Figure 6

Schematic illustration of the molecular mechanisms of Sirtuins in regulating EMT. The scheme illustrates cytosolic (SIRT1 and SIRT2), nuclear (SIRT6 and SIRT7), and mitochondrial (SIRT3, SIRT4, and SIRT5) sirtuins. Some important sirtuins target involved in EMT are indicated, such as SMAD4, which is released upon SIRT1 downregulation, increasing nuclear accumulation of β-catenin and EMT induction. Similarly, SIRT2 increases nuclear β-catenin by deacetylating AKT. Nuclear sirtuins, such as SIRT6 and SIRT7, increase the activity of EMT transcription factors, such as Snail, Slug, and Vimentin. On the other hand, the role of mitochondrial sirtuins is still controversial, with some reports indicating the pro-EMT action of SIRT3 through an increase in β-catenin, while others have shown the anti-EMT action of SIRT3 through the repression of β-catenin and Twist1. Very little is known about SIRT4 and SIRT5, although they seem to prevent EMT induction.

Figure 7

Schematic illustration of how different nanomaterials have been used or could be used to deliver nucleic acids or drugs to modulate hypoxic response and/or sirtuins in order to modulate the EMT process. (A,B) Modulators of sirtuins and/or HIF, such as natural compounds (Piceatannol, Flavonoids), drugs (Metformin, Doxorubicin, Cisplatin), and antibiotics (Acriflavine), could be delivered by polymer-based nanostructures, such as liposomes, Albumin stabilized gold nanoclusters or metal-based nanostructures, such as gold nanoclusters, iron oxide, etc. (C) pathways activated by hypoxia or sirtuins leading to EMT activation could be inhibited, preventing cancer-cell proliferation, tumor growth, invasion, migration and angiogenesis.