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Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator. It plays an important role in cancer development and drug resistance. However, the molecular mechanisms by which CDC20 regulates cellular drug response remain poorly understood. Chromatin-associated CDC20 interactome in breast cancer cells was analyzed by using affinity purification coupled with mass spectrometry. hnRNPU as a CDC20 binding partner was validated by co-immunoprecipitation and immunostaining. The molecular domain, comprising amino acid residues 461–653, on hnRNPU required for its interaction with CDC20 was identified by mapping of interactions. Co-immunoprecipitation showed that CDC20-mediated hnRNPU ubiquitination promotes its interaction with the CTCF and cohesin complex. The effects of CDC20–hnRNPU on nuclear size and chromatin condensation were investigated by analyzing DAPI and H2B-mCherry staining, respectively. The role of CDC20–hnRNPU in tumor progression and drug resistance was examined by CCK-8 cell survival and clonogenic assays. Our study indicates that CDC20-mediated ubiquitination of hnRNPU modulates chromatin condensation by regulating the interaction between hnRNPU and the CTCF–cohesin complex. Dysregulation of the CDC20–hnRNPU axis contributes to tumor progression and drug resistance.

Within the microenvironment of solid tumors, stress associated with deficit of nutrients and oxygen as well as tumor-derived factors triggers the phosphorylation-dependent degradation of the IFNAR1 chain of type I interferon (IFN1) receptor and ensuing suppression of the IFN1 pathway. Here we sought to examine the importance of these events in malignant mammary cells. Expression of non-degradable IFNAR1(S526A) mutant in mouse mammary adenocarcinoma cells stimulated the IFN1 pathway yet did not affect growth of these cells in vitro or ability to form subcutaneous tumors in the syngeneic mice. Remarkably, these cells exhibited a notably accelerated growth when transplanted orthotopically into mammary glands. Importantly, in human patients with either ER+ or ER- breast cancers, high levels of IFNAR1 were associated with poor prognosis. We discuss the putative mechanisms underlying the pro-tumorigenic role of IFNAR1 in malignant breast cells.

Ductal carcinoma in situ (DCIS) makes up a majority of noninvasive breast cancer cases. DCIS is a neoplastic proliferation of epithelial cells within the ductal structure of the breast. Currently, there is little known about the progression of DCIS to invasive ductal carcinoma (IDC), or the molecular etiology behind each DCIS lesion or grade. The DCIS lesions can be heterogeneous in morphology, genetics, cellular biology, and clinical behavior, posing challenges to our understanding of the molecular mechanisms by which approximately half of all DCIS lesions progress to an invasive status. New strategies that pinpoint molecular mechanisms are necessary to overcome this gap in understanding, which is a barrier to more targeted therapy. In this review, we will discuss the etiological factors associated with DCIS, as well as the complexity of each nuclear grade lesion. Moreover, we will discuss the possible molecular features that lead to progression of DCIS to IDC. We will highlight current therapeutic management and areas for improvement.

The ARID1 proteins are mutually exclusive subunits of the BRG1/BRM-associated factor (BAF) complexes that play an important role in chromatin remodeling and regulate many fundamental cell functions. The role of ARID1s is well defined as a tumor-suppressive. The cancer cells evolve different mechanisms to downregulate ARID1s and inactivate their functions. ARID1s are frequently mutated in human cancer. The recent findings of ARID1A/B downregulation at transcriptional and translational levels along with their low levels in human cancers indicate the significance of regulatory mechanisms of ARID1s in cancers. In this review, we present the current knowledge on the regulation and alterations of ARID1 protein expression in human cancers and indicate the importance of regulators of ARID1s as a prognostic marker and in potential therapeutic strategies.

Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of Drosophila models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.

Accumulating evidence suggests that compromised redox signaling enhances the development of hyperactive, pro-inflammatory immune response, which ultimately reduces health- and lifespan. Either underexpression of Peroxiredoxins in the mitochondria (dPrx3 and dPrx5) or overexpression in the ER (dPrx4) has life span shortening effects. Here we show that these effects are associated with activation of the NF-κB –dependent immunity-related/inflammatory genes, which are normally induced in response to infection and ER stress, and constitutively overproduced in old animals. In transgenic flies expressing the ER-localized dPrx4 in the absence of Relish, a Drosophila NF-κB ortholog, the pro-inflammatory effects typically elicited by dPrx4 overexpression were absent. The absence of Relish also significantly rescued the severe shortening of lifespan normally observed in dPrx4 overexpressors. Epistatic analysis also revealed that the dPrx-4 driven overactivation of immune/inflammatory responses was mediated by JAK/STAT signaling. Finally we determined that the activity of dPrx4 in the ER is required to mediate the pro-inflammatory response caused by reduced Prx activity in mitochondria. Thus this study provides evidence for cross-talk between the ER- and mitochondrially-localized peroxiredoxins in regulating the immune response.