Bisphenol A-induced DNA damages promote to lymphoma progression in human lymphoblastoid cells through aberrant CTNNB1 signaling pathway.
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ABSTRACT:
SUBMITTER: Chen YK
PROVIDER: S-EPMC8350018 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are among the most common cancers across the world. Particularly, a large number of patients with CRC also have liver metastasis. Currently, there are just a few targeted drugs against these two kinds of tumors which can only benefit a very small population of patients. Therefore, the need of more effective therapeutic drugs or strategies for these two types of cancers is urgent. PS341 (Bortezomib) is the first proteasome inhibitor drug which has been approved in clinical treatment for multiple myeloma. Here we demonstrated that PS341 negatively regulated HCC and CRC both in vitro and in vivo, including the inhibition of cell proliferation, epithelial-mesenchymal transition (EMT), the expression of stemness-related genes, cell migration and invasiveness. Mechanically, PS341 upregulated the expression of FOXO3, which inhibited the transcriptional activation of CTNNB1. The downregualtion of CTNNB1 led to apoptosis, cell cycle arrest, and the inhibition of migration, invasion, self-renewal and tumor formation of these two cancer types. In sum, our findings shed light on the PS341 mediated targeted therapy against both HCC and CRC in the future.
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Project description:Rationale: This study is to validate the clinicopathologic significance and potential prognostic value of SLP2 in gastric cancer (GC), to investigate the biological function and regulation mechanism of SLP2, and to explore potential therapeutic strategies for GC. Methods: The expression of SLP2 in GC tissues from two cohorts was examined by IHC. The biological function and regulation mechanism of SLP2 and PHB was validated via loss-of-function or gain-of-function experiments. In vitro proliferation detection was used to evaluate the therapeutic effects of Sorafenib. Results: We validated that SLP2 was significantly elevated in GC tissues and its elevation was associated with poor prognosis of patients. Loss of SLP2 drastically suppressed the proliferation of GC cells and inhibited the tumor growth, while SLP2 overexpression promoted the progression of GC. Mechanistically, SLP2 competed against E3 ubiquitin ligase SKP2 to bind with PHB and stabilized its expression. Loss of SLP2 significantly suppressed phosphorylation of Raf1, MEK1/2, ERK1/2 and ELK1. Furthermore, phosphorylated ELK1 could in turn activate transcription of SLP2. Finally, we demonstrated that a Raf1 inhibitor, Sorafenib, was sufficient to inhibit the proliferation of GC cells. Conclusion: Our findings demonstrated a positive feedback loop of SLP2 which leads to acceleration of tumor progression and poor survival of GC patients. This finding also provided evidence for the reason of SLP2 elevation. Moreover, we found that sorafenib might be a potential therapeutic drug for GC and disrupting the interaction between SLP2 and PHB might also serve as a potential therapeutic target in GC.
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Project description:A high percentage of pediatric gliomas and bone tumors reportedly harbor missense mutations at glycine 34 in genes encoding histone variant H3.3. We find that these H3.3 G34 mutations directly alter the enhancer chromatin landscape of mesenchymal stem cells by impeding methylation at lysine 36 on histone H3 (H3K36) by SETD2, but not by the NSD1/2 enzymes. The reduction of H3K36 methylation by G34 mutations promotes an aberrant gain of PRC2-mediated H3K27me2/3 and loss of H3K27ac at active enhancers containing SETD2 activity. This altered histone modification profile promotes a unique gene expression profile that supports enhanced tumor development in vivo. Our findings are mirrored in G34W-containing giant cell tumors of bone where patient-derived stromal cells exhibit gene expression profiles associated with early osteoblastic differentiation. Overall, we demonstrate that H3.3 G34 oncohistones selectively promote PRC2 activity by interfering with SETD2-mediated H3K36 methylation. We propose that PRC2-mediated silencing of enhancers involved in cell differentiation represents a potential mechanism by which H3.3 G34 mutations drive these tumors.
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