ZEB2/TWIST1/PRMT5/NuRD Multicomplex Contributes to the Epigenetic Regulation of EMT and Metastasis in Colorectal Carcinoma.

(1) Background: The EMT plays a crucial role in tumor metastasis, which is the major cause for colorectal carcinoma-related mortality. However, the underlying regulators and mechanisms of EMT in CRC metastasis are still poorly understood; (2) Methods: The transcriptional regulators of EMT in CRC and their functions were examined using RT2212PCR, Western blotting, and luciferase reporter assay. The components of ZEB2/TWIST1 complex and their mutual interactions were identified via affinity purification, mass spectrometry, co-immunoprecipitation, and pull-down experiments. The functional mechanisms of ZEB2/TWIST1/PRMT5/NuRD axis were determined by chromatin immunoprecipitation and luciferase reporter assay. The contribution of ZEB2/TWIST1/PRMT5/NuRD complex in the CRC metastasis was investigated using wound healing, transwell assay, and in vivo xenograft mouse model; (3) Results: We found that ZEB2 and TWIST1 were both significantly upregulated in CRC tissues and EMT of CRC cells. ZEB2 could recruit TWIST1 to the E-cadherin promoter and synergistically repressed its transcription. In addition, ZEB2 physically interacted with TWIST1, PRMT5, and the nucleosome remodeling and deacetylase (NuRD) complex to form a novel repressive multicomplex, leading to epigenetic silencing of E-cadherin in CRC cells. Notably, the combined inhibition of ZEB2 and TWIST1 and epigenetic inhibition markedly reduced CRC metastasis in mice; (4) Conclusions: We revealed for the first time that ZEB2 could recruit TWIST1, PRMT5, and NuRD to form a repressive multicomplex and epigenetically suppresses the transcription of E-cadherin, thereby inducing the EMT process and metastasis in CRC. Our results also confirmed the therapeutic potential of epigenetic inhibitors in CRC.

The behavioural and neuropathologic sexual dimorphism and absence of MIP-3α in tau P301S mouse model of Alzheimer's disease.

BACKGROUND: Tau hyper-phosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and related tauopathies, and has gained prominence in therapeutic development for AD. To elucidate the pathogenic mechanisms underlying AD and evaluate therapeutic approaches targeting tau, numerous transgenic mouse models that recapitulate critical AD-like pathology have been developed. Tau P301S transgenic mice is one of the most widely used mouse models in AD research. Extensive studies have demonstrated that sex significantly influences AD pathology, behavioral status, and therapeutic outcomes, suggesting that studies using mouse models of AD must consider sex- and age-related differences in neuropathology, behavior, and plasma content. METHOD: We systematically investigated differences in tau P301S transgenic mice (PS19 line) and wildtype littermates of different sex behavioral performance, tau neuropathology, and biomarkers in plasma and brain. RESULTS: Male P301S transgenic mice exhibited significant changes in weight loss, survival rate, clasping, kyphosis, composite phenotype assessment, nest building performance, tau phosphorylation at Ser202/Thr205, and astrocyte activation compared to that of wild-type littermates. In contrast, female P301S transgenic mice were only sensitive in the Morris water maze and open field test. In addition, we characterized the absence of macrophage-inflammatory protein (MIP-3α) and the upregulation of interferon (IFN)-γ, interleukin (IL)-5, and IL-6 in the plasma of P301S transgenic mice, which can be served as potential plasma biomarkers in P301S Tg mice. Male P301S transgenic mice expressed more monokine induced by IFN-γ (MIG), tumor necrosis factor-α (TNF-α), IL-10, and IL-13 than those of female P301S mice. CONCLUSION: Our findings highlight sexual dimorphism in the behavior, neuropathology, and plasma proteins in tau P301S transgenic AD mice, indicating that the use of male P301S transgenic mice may be more suitable for assessing anti-phosphorylated tau therapeutic strategies for AD and related tauopathies, and the MIP-3α may be a new potential plasma biomarker.

USP28 contributes to the proliferation and metastasis of gastric cancer.

USP28, a member of the deubiquitinating enzymes family, plays a vital role in the physiological process of cell proliferation, differentiation and apoptosis, DNA repair, immune response, and stress response. USP28 has been reported to be overexpressed in bladder cancer, colon cancer, breast carcinomas, and so on. Nevertheless, the role of USP28 in gastric cancer has not yet been investigated. In our study, we examined the USP28 expression in 87 paired samples of gastric cancer and normal gastric tissues. We found that USP28 was overexpressed in gastric cancer compared with normal gastric tissues (P < 0.01), and its overexpression was related to the degree of differentiation and metastases. Inhibiting USP28 expression in vitro suppressed the proliferation and invasion of gastric cancer cells by downregulating lysine specific demethylase 1. On the basis of our data, it can be concluded that USP28 may be a novel therapeutic target for gastric cancer.

Lysine-specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC-803.

B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer.