The involvement of the homologous to E6-AP carboxyl terminus (HECT)-type E3s in crucial signaling pathways implicated in tumorigenesis is presently an area of intense research and extensive ...scientific interest. This review highlights recent discoveries on the ubiquitin-mediated degradation of crucial tumor suppressor molecules catalyzed by the HECT-type E3s. By providing a portrait of their protein targets, we intend to link the substrate specificity of HECT-type E3s with their contribution to tumorigenesis. Moreover, we discuss the relevance of targeting the HECT E3s, through the development of small-molecule inhibitors, as an anticancer therapeutic strategy.
Significance p63, the sister homolog of p53, is a master regulator of epithelial stem cell (SC) biology. p63 is indeed intimately implicated in the maintenance of the self-renewal capacity of ...stratified epithelia and their derivatives, including the mammary gland. Although the physiological role of p63 in normal mammary SCs is now acknowledged, proof of its implications in breast cancer SCs remains elusive. Here, we find that mammary cancer stem cells (CSCs) possess increased levels of p63 expression compared with normal progenitors. p63 promotes self-renewal and expansion of mammary CSCs and breast tumor growth in vivo. Additionally, this study provides a link between p63 and the Sonic Hedgehog signaling pathway in the regulation of breast cancer stemness.
The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog ( Shh ), GLI family zinc finger 2 ( Gli2 ), and Patched1 ( Ptch1 ) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of fatty deposits in the inner walls of vessels. These plaques restrict blood flow and lead to complications such ...as heart attack or stroke. The development of atherosclerosis is influenced by a variety of factors, including age, genetics, lifestyle, and underlying health conditions such as high blood pressure or diabetes. Atherosclerotic plaques in stable form are characterized by slow growth, which leads to luminal stenosis, with low embolic potential or in unstable form, which contributes to high risk for thrombotic and embolic complications with rapid clinical onset. In this complex scenario of atherosclerosis, macrophages participate in the whole process, including the initiation, growth and eventually rupture and wound healing stages of artery plaque formation. Macrophages in plaques exhibit high heterogeneity and plasticity, which affect the evolving plaque microenvironment, e.g., leading to excessive lipid accumulation, cytokine hyperactivation, hypoxia, apoptosis and necroptosis. The metabolic and functional transitions of plaque macrophages in response to plaque microenvironmental factors not only influence ongoing and imminent inflammatory responses within the lesions but also directly dictate atherosclerotic progression or regression. In this review, we discuss the origin of macrophages within plaques, their phenotypic diversity, metabolic shifts, and fate and the roles they play in the dynamic progression of atherosclerosis. It also describes how macrophages interact with other plaque cells, particularly T cells. Ultimately, targeting pathways involved in macrophage polarization may lead to innovative and promising approaches for precision medicine. Further insights into the landscape and biological features of macrophages within atherosclerotic plaques may offer valuable information for optimizing future clinical treatment for atherosclerosis by targeting macrophages.
The ubiquitin proteasome system (UPS) plays a role in the regulation of most cellular pathways, and its deregulation has been implicated in a wide range of human pathologies that include cancer, ...neurodegenerative and immunological disorders and viral infections. Targeting the UPS by small molecular regulators thus provides an opportunity for the development of therapeutics for the treatment of several diseases. The proteasome inhibitor Bortezomib was approved for treatment of hematologic malignancies by the FDA in 2003, becoming the first drug targeting the ubiquitin proteasome system in the clinic. Development of drugs targeting specific components of the ubiquitin proteasome system, however, has lagged behind, mainly due to the complexity of the ubiquitination reaction and its outcomes. However, significant advances have been made in recent years in understanding the molecular nature of the ubiquitination system and the vast variety of cellular signals that it produces. Additionally, improvement of screening methods, both in vitro and in silico, have led to the discovery of a number of compounds targeting components of the ubiquitin proteasome system, and some of these have now entered clinical trials. Here, we discuss the current state of drug discovery targeting E3 ligases and the opportunities and challenges that it provides.
The ubiquitin system is a dynamic regulatory pathway controlling the activity, subcellular localization and stability of a myriad of cellular proteins, which in turn affects cellular homeostasis ...through the regulation of a variety of signaling cascades. Aberrant activity of key components of the ubiquitin system has been functionally linked with numerous human diseases including the initiation and progression of human tumors. In this review, we will contextualize the importance of the two main components of the ubiquitin system, the E3 ubiquitin ligases (E3s) and deubiquitinating enzymes (DUBs), in the etiology of squamous cell carcinomas (SCCs). We will discuss the signaling pathways regulated by these enzymes, emphasizing the genetic and molecular determinants underlying their deregulation in SCCs.
Head and neck squamous cell carcinoma (HNSCC) is characterized by high proliferation and limited differentiation. The altered expression of the p53 family members, and specifically of p63, represents ...a pivotal event in the pathogenesis of HNSCC. Physiologically, p63 affects metabolism through the direct transactivation of the enzyme hexokinase 2, and subsequently controls the proliferation of epithelial cells; nonetheless, its role in cancer metabolism is still largely unclear. The high energetic demand of cancer and the consequent needs of a metabolic reshape, also involve the serine and glycine catabolic and anabolic pathways, including the one carbon metabolism (OCM), to produce energetic compounds (purines) and to maintain cellular homeostasis (glutathione and S-adenosylmethionine).
The involvement in serine/glycine starvation by other p53 family members has been reported, including HNSCC. Here, we show that in HNSCC p63 controls the expression of the enzymes regulating the serine biosynthesis and one carbon metabolism. p63 binds the promoter region of genes involved in the serine biosynthesis as well as in the one carbon metabolism. p63 silencing in a HNSCC cell line affects the mRNA and protein levels of these selected enzymes. Moreover, the higher expression of TP63 and its target enzymes, negatively impacts on the overall survival of HNSCC patients.
These data indicate a direct role of p63 in the metabolic regulation of HNSCC with significant clinical effects.
The uc.291 transcript controls keratinocytes differentiation by physical interaction with ACTL6A and subsequent induction of transcription of the genes belonging to the epidermal differentiation ...complex (EDC). Uc.291 is also implicated in the dedifferentiation phenotype seen in poorly differentiated cutaneous squamous cell carcinomas. Here, we would like to investigate the contribution of uc.291 to the unbalanced differentiation state of keratinocytes observed in hyperproliferative skin disorders, e. g., psoriasis. Psoriasis is a multifactorial inflammatory disease, caused by alteration of keratinocytes homeostasis. The imbalanced differentiation state, triggered by the infiltration of immune cells, represents one of the events responsible for this pathology. In the present work, we explore the role of uc.291 and its interactor ACTL6A in psoriasis skin, using quantitative real-time PCR (RT-qPCR), immunohistochemistry and bioinformatic analysis of publicly available datasets. Our data suggest that the expression of the uc.291 and of EDC genes loricrin and filaggrin (LOR, FLG) is reduced in lesional skin compared to nonlesional skin of psoriatic patients; conversely, the mRNA and protein level of ACTL6A are up-regulated. Furthermore, we provide evidence that the expression of uc.291, FLG and LOR is reduced, while ACTL6A mRNA is up-regulated, in an in vitro psoriasis-like model obtained by treating differentiated keratinocytes with interleukin 22 (IL-22). Furthermore, analysis of a publicly available dataset of human epidermal keratinocytes treated with IL-22 (GSE7216) confirmed our in vitro results. Taken together, our data reveal a novel role of uc.291 and its functional axis with ACTL6A in psoriasis disorder and a proof of concept that biological inhibition of this molecular axis could have a potential pharmacological effect against psoriasis and, in general, in skin diseases with a suppressed differentiation programme.
Autophagy is a conserved self‐eating process that delivers cytoplasmic material to the lysosome to allow degradation of intracellular components, including soluble, unfolded and aggregated proteins, ...damaged organelles, and invading microorganisms. Autophagy provides a homeostatic control mechanism and is essential for balancing sources of energy in response to nutrient stress. Autophagic dysfunction or dysregulation has been implicated in several human pathologies, including cancer and neurodegeneration, and its modulation has substantial potential as a therapeutic strategy. Given the relevant clinical and therapeutic implications of autophagy, there is emerging intense interest in the identification of the key factors regulating the components of the autophagic machinery. Various post‐translational modifications, including ubiquitylation, have been implicated in autophagy control. The list of the E3 ubiquitin protein ligases involved in the regulation of several steps of the autophagic process is continuously growing. In this review, we will focus on recent advances in the understanding of the role of the homologous to the E6AP carboxyl terminus‐type E3 ubiquitin ligases in autophagy control.
Ubiquitylation is a relevant determinant of autophagy regulation. E3 ubiquitin ligases promote the attachment of ubiquitin to target substrates. In this review, we will discuss recent evidence linking homologous to the E6AP carboxyl terminus (HECT)‐type E3 ubiquitin ligases to autophagy. Modification of substrates by HECT E3 ligases affects different steps of the autophagic process: initiation, nucleation of the phagophore, cargo selection, and autophagosome formation.
Natural ageing of organisms and corresponding age-related diseases result mainly from stem cell ageing and "inflammaging". Mesenchymal stem cells (MSCs) exhibit very high immune-regulating capacity ...and are promising candidates for immune-related disease treatment. However, the effect of MSC application is not satisfactory for some patients, especially in elderly individuals. With ageing, MSCs undergo many changes, including altered cell population reduction and differentiation ability, reduced migratory and homing capacity and, most important, defective immunosuppression. It is necessary to explore the relationship between the "inflammaging" and aged MSCs to prevent age-related diseases and increase the therapeutic effects of MSCs. In this review, we discuss changes in naturally ageing MSCs mainly from an inflammation perspective and propose some ideas for rejuvenating aged MSCs in future treatments.
Ubiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy ...and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.
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