The E3 ubiquitin ligase CHIP drives monoubiquitylation-mediated nuclear import of the tumor suppressor PTEN.

Monoubiquitylation is a principal mechanism driving nuclear translocation of the protein PTEN (phosphatase and tensin homolog deleted on chromosome ten). In this study, we describe a novel mechanism wherein the protein CHIP (C-terminus of Hsc70-interacting protein) mediates PTEN monoubiquitylation, leading to its nuclear import. Western blot analysis revealed a rise in both nuclear and total cellular PTEN levels under monoubiquitylation-promoting conditions, an effect that was abrogated by silencing CHIP expression. We established time-point kinetics of CHIP-mediated nuclear translocation of PTEN using immunocytochemistry and identified a role of karyopherin α1 (KPNA1) in facilitating nuclear transport of monoubiquitylated PTEN. We further established a direct interaction between CHIP and PTEN inside the nucleus, with CHIP participating in either polyubiquitylation or monoubiquitylation of nuclear PTEN. Finally, we showed that oxidative stress enhanced CHIP-mediated nuclear import of PTEN, which resulted in increased apoptosis, and decreased cell viability and proliferation, whereas CHIP knockdown counteracted these effects. To the best of our knowledge, this is the first report elucidating non-canonical roles for CHIP on PTEN, which we establish here as a nuclear interacting partner of CHIP.

COVID-19: Clinical status of vaccine development to date.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced COVID-19 is a complicated disease. Clinicians are continuously facing difficulties to treat infected patients using the principle of repurposing of drugs as no specific drugs are available to treat COVID-19. To minimize the severity and mortality, global vaccination is the only hope as a potential preventive measure. After a year-long global research and clinical struggle, 165 vaccine candidates have been developed and some are currently still in the pipeline. A total of 28 candidate vaccines have been approved for use and the remainder are in different phases of clinical trials. In this comprehensive report, the authors aim to demonstrate, classify and provide up-to-date clinical trial status of all the vaccines discovered to date and specifically focus on the approved candidates. Finally, the authors specifically focused on the vaccination of different types of medically distinct populations.

Extracellular Vesicles in Glioma: From Diagnosis to Therapy.

Increasing evidence indicates that extracellular vesicles (EVs) secreted from tumor cells play a key role in the overall progression of the disease state. EVs such as exosomes are secreted by a wide variety of cells and transport a varied population of proteins, lipids, DNA, and RNA species within the body. Gliomas constitute a significant proportion of all primary brain tumors and majority of brain malignancies. Glioblastoma multiforme (GBM) represents grade IV glioma and is associated with very poor prognosis despite the cumulative advances in diagnostic procedures and treatment strategies. Here, the authors describe the progress in understanding the role of EVs, especially exosomes, in overall glioma progression, and how new research is unraveling the utilities of exosomes in glioma diagnostics and development of next-generation therapeutic systems. Finally, based on an understanding of the latest scientific literature, a model for the possible working of therapeutic exosomes in glioma treatment is proposed.

Lactation-Based Maternal Educational Immunity Crosses MHC Class I Barriers and Can Impart Th1 Immunity to Th2-Biased Recipients.

We have previously demonstrated lactational transfer of T cell-based immunity from dam to foster pup. In the short term, a significant part of transferred immunity is passive cellular immunity. However, as time progresses, this is replaced by what we have described as maternal educational immunity such that by young adulthood, all immune cells responding to a foster dam immunogen are the product of the foster pup's thymus. To reduce confounding factors, this original demonstration used congenic/syngeneic dam and foster pup pairs. In this study, we investigated lactational transfer of immunity to Mycobacterium tuberculosis in MHC class I-mismatched animals, as well as from Th1-biased dams to Th2-biased foster pups. Using immunized C57BL/6J dams, lactational transfer to nonimmunized BALB/cJ foster pups resulted in much greater immunity than direct immunization in 5-wk-old pups (ex vivo assay of pup splenocytes). At this age, 82% of immunogen-responding cells in the pup spleen were produced through maternal educational immunity. FVB/NJ nonimmunized foster recipients had a greater number of maternal cells in the spleen and thymus but a much larger percentage was Foxp3+, resulting in equivalent immunity to direct immunization. Depletion of maternal Foxp3+ cells from pup splenocytes illustrated a substantial role for lactationally transferred dam regulatory T cells in suppression of the ex vivo response in FVB/NJ, but not BALB/cJ, recipients. We conclude that lactational transfer of immunity can cross MHC class I barriers and that Th1 immunity can be imparted to Th2-biased offspring; in some instances, it can be greater than that achieved by direct immunization.

Maternal Milk T Cells Drive Development of Transgenerational Th1 Immunity in Offspring Thymus.

Using multiple murine foster-nursing protocols, thereby eliminating placental transfer and allowing a distinction between dam- and pup-derived cells, we show that foster nursing by an immunized dam results in development of CD8(+) T cells in nonimmunized foster pups that are specific for Ags against which the foster dam was immunized (Mycobacterium tuberculosis or Candida albicans). We have dubbed this process "maternal educational immunity" to distinguish it from passive cellular immunity. Of the variety of maternal immune cells present in milk, only T cells were detected in pup tissues. Maternal T cells, a substantial percentage of which were CD4(+)MHC class II(+), accumulated in the pup thymus and spleen during the nursing period. Further analysis of maternal cells in the pup thymus showed that a proportion was positive for maternal immunogen-specific MHC class II tetramers. To determine the outcome of Ag presentation in the thymus, the maternal or foster pup origin of immunogen-responding CD8(+) cells in foster pup spleens was assessed. Whereas ∼10% were maternally derived in the first few weeks after weaning, all immunogen-responding CD8(+) T cells were pup derived by 12 wk of age. Pup-derived immunogen-responsive CD8(+) cells persisted until at least 1 y of age. Passive cellular immunity is well accepted and has been demonstrated in the human population. In this study, we show an arguably more important role for transferred immune cells: the direction of offspring T cell development. Harnessing maternal educational immunity through prepregnancy immunization programs has potential for improvement of infant immunity.

Simultaneous inhibition of key growth pathways in melanoma cells and tumor regression by a designed bidentate constrained helical peptide.

Protein-protein interactions are part of a large number of signaling networks and potential targets for drug development. However, discovering molecules that can specifically inhibit such interactions is a major challenge. S100B, a calcium-regulated protein, plays a crucial role in the proliferation of melanoma cells through protein-protein interactions. In this article, we report the design and development of a bidentate conformationally constrained peptide against dimeric S100B based on a natural tight-binding peptide, TRTK-12. The helical conformation of the peptide was constrained by the substitution of α-amino isobutyric acid--an amino acid having high helical propensity--in positions which do not interact with S100B. A branched bidentate version of the peptide was bound to S100B tightly with a dissociation constant of 8 nM. When conjugated to a cell-penetrating peptide, it caused growth inhibition and rapid apoptosis in melanoma cells. The molecule exerts antiproliferative action through simultaneous inhibition of key growth pathways, including reactivation of wild-type p53 and inhibition of Akt and STAT3 phosphorylation. The apoptosis induced by the bidentate constrained helix is caused by direct migration of p53 to mitochondria. At moderate intravenous dose, the peptide completely inhibits melanoma growth in a mouse model without any significant observable toxicity. The specificity was shown by lack of ability of a double mutant peptide to cause tumor regression at the same dose level. The methodology described here for direct protein-protein interaction inhibition may be effective for rapid development of inhibitors against relatively weak protein-protein interactions for de novo drug development.

MGMT in TMZ-based glioma therapy: Multifaceted insights and clinical trial perspectives.

Temozolomide (TMZ) is the most preferred and approved chemotherapeutic drug for either first- or second-line chemotherapy for glioma patients across the globe. In glioma patients, resistance to treatment with alkylating drugs like TMZ is known to be conferred by exalted levels of MGMT gene expression. On the contrary, epigenetic silencing through MGMT gene promoter methylation leading to subsequent reduction in MGMT transcription and protein expression, is predicted to have a response favoring TMZ treatment. Thus, MGMT protein level in cancer cells is a crucial determining factor in indicating and predicting the choice of alkylating agents in chemotherapy or choosing glioma patients directly for a second line of treatment. Thus, in-depth research is necessary to achieve insights into MGMT gene regulation that has recently enticed a fascinating interest in epigenetic, transcriptional, post-transcriptional, and post-translational levels. Furthermore, MGMT promoter methylation, stability of MGMT protein, and related subsequent adaptive responses are also important contributors to strategic developments in glioma therapy. With applications to its identification as a prognostic biomarker, thus predicting response to advanced glioma therapy, this review aims to concentrate on the mechanistic role and regulation of MGMT gene expression at epigenetic, transcriptional, post-transcriptional, and post-translational levels functioning under the control of multiple signaling dynamics.

E3 ubiquitin ligases in lung cancer: Emerging insights and therapeutic opportunities.

Aim In this review, we have attempted to provide the readers with an updated account of the role of a family of proteins known as E3 ligases in different aspects of lung cancer progression, along with insights into the deregulation of expression of these proteins during lung cancer. A detailed account of the therapeutic strategies involving E3 ligases that have been developed or currently under development has also been provided in this review. MATERIALS AND METHODS: The review article employs extensive literature search, along with differential gene expression analysis of lung cancer associated E3 ligases using the DESeq2 package in R, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/). Protein expression analysis of CPTAC lung cancer samples was carried out using the UALCAN webtool (https://ualcan.path.uab.edu/index.html). Assessment of patient overall survival (OS) in response to high and low expression of selected E3 ligases was performed using the online Kaplan-Meier plotter (https://kmplot.com/analysis/index.php?p=background). KEY FINDINGS: SIGNIFICANCE: The review provides an in-depth understanding of the role of E3 ligases in lung cancer progression and an up-to-date account of the different therapeutic strategies targeting oncogenic E3 ligases for improved lung cancer management.

The chaperone-assisted E3 ligase C terminus of Hsc70-interacting protein (CHIP) targets PTEN for proteasomal degradation.

The tumor suppressor, PTEN is key to the regulation of diverse cellular processes, making it a prime candidate to be tightly regulated. The PTEN level is controlled in a major way by E3 ligase-mediated degradation through the Ubiquitin-Proteasome System (UPS). Nedd 4-1, XIAP, and WWP2 have been shown to maintain PTEN turnover. Here, we report that CHIP, the chaperone-associated E3 ligase, induces ubiquitination and regulates the proteasomal turnover of PTEN. It was apparent from our findings that PTEN transiently associates with the molecular chaperones and thereby gets diverted to the degradation pathway through its interaction with CHIP. The TPR domain of CHIP and parts of the N-terminal domain of PTEN are required for their interaction. Overexpression of CHIP leads to elevated ubiquitination and a shortened half-life of endogenous PTEN. On the other hand, depletion of endogenous CHIP stabilizes PTEN. CHIP is also shown to regulate PTEN-dependent transcription presumably through its down-regulation. PTEN shared an inverse correlation with CHIP in human prostate cancer patient samples, thereby triggering the prospects of a more complex mode of PTEN regulation in cancer.

Mechanism of ß-catenin-mediated transcriptional regulation of epidermal growth factor receptor expression in glycogen synthase kinase 3 ß-inactivated prostate cancer cells.

Wnt/ß-catenin and EGFR pathways are important in cancer development and often aberrantly activated in human cancer. However, it is very important to understand the mechanism responsible for this activation and the relation between them. Here, we report the mechanism of EGFR expression by transcriptionally active ß-catenin in GSK3ß-inactivated prostate cancer cells that eventually leads to its enhanced proliferation and survival. Expressions of ß-catenin and EGFR are elevated in various cancers specifically in prostate cancer cells, DU145. When GSK3ß is inactivated in these cells, ß-catenin gets stabilized, phosphorylated at Ser-552 by protein kinase A, accumulates in the nucleus, and regulates the expression of its target genes that include EGFR. Chromatin immunoprecipitation (ChIP) and promoter analysis revealed that the EGFR promoter gets occupied by transcriptionally active ß-catenin when elevated in GSK3ß-inactivated cells. This phenomenon not only leads to increased expression of EGFR but also initiates the activation of its downstream molecules such as ERK1/2 and Stat3, ultimately resulting in up-regulation of multiple genes involved in cell proliferation and survival.

DEAD-box RNA helicases with special reference to p68: Unwinding their biology, versatility, and therapeutic opportunity in cancer.

In the era of advancement, the entire world continues to remain baffled by the increased rate of progression of cancer. There has been an unending search for novel therapeutic targets and prognostic markers to curb the oncogenic scenario. The DEAD-box RNA helicases are a large family of proteins characterized by their evolutionary conserved D-E-A-D (Asp-Glu-Ala-Asp) domain and merit consideration in the oncogenic platform. They perform multidimensional functions in RNA metabolism and also in the pathology of cancers. Their biological role ranges from ribosome biogenesis, RNA unwinding, splicing, modification of secondary and tertiary RNA structures to acting as transcriptional coactivators/repressors of various important oncogenic genes. They also play a crucial role in accelerating oncogenesis by promoting cell proliferation and metastasis. DDX5 (p68) is one of the archetypal members of this family of proteins and has gained a lot of attention due to its oncogenic attribute. It is found to be overexpressed in major cancer types such as colon, brain, breast, and prostate cancer. It exhibits its multifaceted nature by not only coactivating genes implicated in cancers but also mediating crosstalk across major signaling pathways in cancer. Therefore, in this review, we aim to illustrate a comprehensive overview of DEAD-box RNA helicases especially p68 by focusing on their multifaceted roles in different cancers and the various signaling pathways affected by them. Further, we have also briefly discoursed the therapeutic interventional approaches with the DEAD-box RNA helicases as the pharmacological targets for designing inhibitors to pave way for cancer therapy.

USP7 - a crucial regulator of cancer hallmarks.

Over the course of three decades of study, the deubiquitinase Herpesvirus associated Ubiquitin-Specific Protease/Ubiquitin-Specific Protease 7 (HAUSP/USP7) has gradually come to be recognized as a crucially important molecule in cellular physiology. The fact that USP7 is overexpressed in a number of cancers, including breast, prostate, colorectal, and lung cancers, supports the idea that USP7 is also an important regulator of tumorigenesis. In this review, we discuss USP7's function in relation to the cancer hallmarks described by Hanahan and Weinberg. This post-translational modifier can support increased proliferation, block unfavorable growth signals, stop cell death, and support an unstable cellular genome by manipulating key players in the pertinent signalling circuit. It is interesting to note that USP7 also aids in the stabilization of molecules that support angiogenesis and metastasis. Targeting USP7 has now emerged as a crucial component of USP7 research because pharmacological inhibition of USP7 supports p53-mediated cell cycle arrest and apoptosis. Efficacious USP7 inhibition is currently being investigated in both synthetic and natural compounds, but issues with selectivity and a lack of co-crystal structure have hindered USP7 inhibition from being tested in clinical settings. Moreover, the development of new, more effective USP7 inhibitors and their encouraging implications by numerous groups give us a glimmer of hope for USP7-targeting medications as effective substitutes for hazardous cancer chemotherapeutics.

The DEAD-box RNA helicase DDX5 (p68) and ß-catenin: The crucial regulators of FOXM1 gene expression in arbitrating colorectal cancer.

Forkhead box M1 (FOXM1), a vital member of the Forkhead box family of transcription factors, helps in mediating oncogenesis. However, limited knowledge exists regarding the mechanistic insights into the FOXM1 gene regulation. DDX5 (p68), an archetypal member of the DEAD-box family of RNA helicases, shows multifaceted action in cancer progression by arbitrating RNA metabolism and transcriptionally coactivating transcription factors. Here, we report a novel mechanism of alliance between DDX5 (p68) and the Wnt/ß-catenin pathway in regulating FOXM1 gene expression and driving colon carcinogenesis. Initial bioinformatic analyses highlighted elevated expression levels of FOXM1 and DDX5 (p68) in colorectal cancer datasets. Immunohistochemical assays confirmed that FOXM1 showed a positive correlation with DDX5 (p68) and ß-catenin in both normal and colon carcinoma patient samples. Overexpression of DDX5 (p68) and ß-catenin increased the protein and mRNA expression profiles of FOXM1, and the converse correlation occurred during downregulation. Mechanistically, overexpression and knockdown of DDX5 (p68) and ß-catenin elevated and diminished FOXM1 promoter activity respectively. Additionally, Chromatin immunoprecipitation assay demonstrated the occupancy of DDX5 (p68) and ß-catenin at the TCF4/LEF binding element (TBE) sites on the FOXM1 promoter. Thiostrepton delineated the effect of FOXM1 inhibition on cell proliferation and migration. Colony formation assay, migration assay, and cell cycle data reveal the importance of the DDX5 (p68)/ß-catenin/FOXM1 axis in oncogenesis. Collectively, our study mechanistically highlights the regulation of FOXM1 gene expression by DDX5 (p68) and ß-catenin in colorectal cancer.

DDX5 (p68) orchestrates ß-catenin, RelA and SP1 mediated MGMT gene expression in human colon cancer cells: Implication in TMZ chemoresistance.

DDX5 (p68) upregulation has been linked with various cancers of different origins, especially Colon Adenocarcinomas. Similarly, across cancers, MGMT has been identified as the major contributor of chemoresistance against DNA alkylating agents like Temozolomide (TMZ). TMZ is an emerging potent chemotherapeutic agent across cancers under the arena of drug repurposing. Recent studies have established that patients with open MGMT promoters are prone to be innately resistant or acquire resistance against TMZ compared to its closed conformation. However, not much is known about the transcriptional regulation of MGMT gene in the context of colon cancer. This necessitates studying MGMT gene regulation which directly impacts the cellular potential to develop chemoresistance against alkylating agents. Our study aims to uncover an unidentified mechanism of DDX5-mediated MGMT gene regulation. Experimentally, we found that both mRNA and protein expression levels of MGMT were elevated in response to p68 overexpression in multiple human colon cancer cell lines and vice-versa. Since p68 cannot directly interact with the MGMT promoter, transcription factors viz., ß-catenin, RelA (p65) and SP1 were also studied as reported contributors. Through co-immunoprecipitation and GST-pull-down studies, p68 was established as an interacting partner of SP1 in addition to ß-catenin and NF-κB (p50-p65). Mechanistically, luciferase reporter and chromatin-immunoprecipitation assays demonstrated that p68 interacts with the MGMT promoter via TCF4-LEF, RelA and SP1 sites to enhance its transcription. To the best of our knowledge, this is the first report of p68 as a transcriptional co-activator of MGMT promoter and our study identifies p68 as a novel and master regulator of MGMT gene expression.

USP7 imparts partial EMT state in colorectal cancer by stabilizing the RNA helicase DDX3X and augmenting Wnt/ß-catenin signaling.

Epithelial mesenchymal transition (EMT) is a fundamental and highly regulated process that is normally observed during embryonic development and tissue repair but is deregulated during advanced cancer. Classically, through the process of EMT, cancer cells gradually transition from a predominantly epithelial phenotype to a more invasive mesenchymal phenotype. Increasing studies have, however, brought into light the existence of unique intermediary states in EMT, often referred to as partial EMT states. Through our studies we have found the deubiquitinase USP7 to be strongly associated with the development of such a partial EMT state in colon cancer cells, characterized by the acquisition of mesenchymal characteristics but without the reduction in epithelial markers. We found USP7 to be overexpressed in colon adenocarcinomas and to be closely associated with advancing tumor stage. We found that functional inhibition or knockdown of USP7 is associated with a marked reduction in mesenchymal markers and in overall migration potential of cancer cells. Starting off with a proteomics-based approach we were able to identify and later on verify the DEAD box RNA helicase DDX3X to be an interacting partner of USP7. We then went on to show that USP7, through the stabilization of DDX3X, augments Wnt/ß-catenin signaling, which has previously been shown to be greatly associated with colorectal cancer cell invasiveness. Our results indicate USP7 as a novel key player in establishing a partial mesenchymal phenotype in colorectal cancer.

COVID-19 therapeutics: Clinical application of repurposed drugs and futuristic strategies for target-based drug discovery.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.

Neurological damages in COVID-19 patients: Mechanisms and preventive interventions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, causes coronavirus disease 2019 (COVID-19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi-organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia-driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS-CoV-2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID-19 associated damage to the central nervous system, patients need special care to prevent multi-organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant-based prevention therapies for COVID-19-associated neurological damage that leads to multi-organ failure.

Targeting PD-1/PD-L1 in cancer immunotherapy: An effective strategy for treatment of triple-negative breast cancer (TNBC) patients.

Maintaining the balance between eliciting immune responses against foreign proteins and tolerating self-proteins is crucial for maintenance of homeostasis. The functions of programmed death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells. However, cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation. Over the past few years' rapid development in cancer immunotherapy has opened a new avenue in cancer treatment. Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy. Initially, immune checkpoint monotherapies were not very successful, making breast cancer less immunogenic. Although, recent reports support the presence of tumor infiltrating lymphocytes (TILs) in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy, which is effective in PD-L1 positive patients. Recently, anti-PD-1 (pembrolizumab) and anti-PD-L1 (atezolizumab) gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research. Likewise, this article gathered understanding of PD-1 and PD-L1 in recent years, their signaling networks, interaction with other molecules, regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy. Additionally, authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy.

A small HDM2 antagonist peptide and a USP7 inhibitor synergistically inhibit the p53-HDM2-USP7 circuit.

HDM2, an E3 ubiquitin ligase, is a crucial regulator of many proliferation-related pathways. It is also one of the primary regulators of p53. USP7, a deubiquitinase, also plays a key role in the regulation of both p53 and HDM2, thus forming a small regulatory network with them. This network has emerged as an important drug target. Development of a synergistic combination targeting both proteins is desirable and important for regulating this module. We have developed a small helically constrained peptide that potently inhibited p53-HDM2 interaction and exerted anti-proliferative effects on p53+/+ cells. A combination of this peptide-when attached to cell entry and nuclear localization tags-and a USP7 inhibitor showed synergistic anti-proliferative effects against cells harboring wild-type alleles of p53. Synergistic inhibition of two important drug targets may lead to novel therapeutic strategies.

Ubiquitination and deubiquitination in the regulation of epithelial-mesenchymal transition in cancer: Shifting gears at the molecular level.

The process of conversion of non-motile epithelial cells to their motile mesenchymal counterparts is known as epithelial-mesenchymal transition (EMT), which is a fundamental event during embryonic development, tissue repair, and for the maintenance of stemness. However, this crucial process is hijacked in cancer and becomes the means by which cancer cells acquire further malignant properties such as increased invasiveness, acquisition of stem cell-like properties, increased chemoresistance, and immune evasion ability. The switch from epithelial to mesenchymal phenotype is mediated by a wide variety of effector molecules such as transcription factors, epigenetic modifiers, post-transcriptional and post-translational modifiers. Ubiquitination and de-ubiquitination are two post-translational processes that are fundamental to the ubiquitin-proteasome system (UPS) of the cell, and the shift in equilibrium between these two processes during cancer dictates the suppression or activation of different intracellular processes, including EMT. Here, we discuss the complex and dynamic relationship between components of the UPS and EMT in cancer.