Oral squamous cell carcinoma (OSCC) is a common malignancy with dismal prognosis without effective therapeutic options in advanced cases. The evolution from oral potentially malignant disorders to OSCC has poorly described underlying epigenetic features. With the ability of silencing or activation of vital genes, histone modifications’ and modifiers’ potentiality for early diagnosis, prognosis predicting, and therapy in OSCC were evaluated by extensive epigenetic studies. This review investigates the roles of dysregulated histone modifications and the associated modifying enzymes in OSCC onset and progression. Also, we focus on the current advances of histone modifications as therapeutic targets and the potential value of epi‐drugs.
Early-onset preeclampsia (PE) is a pregnancy complication that can lead to severe adverse maternal and fetal outcomes. However, the mechanisms underlying the development of early-onset PE are not fully understood. Ribosomal protein L39 (RPL39) is a member of the S39E family of ribosomal proteins that plays an important role in stem cell self-renewal, cancer metastasis, and chemoresistance. In this study, we aimed to explore the potential function of RPL39 in placental trophoblast cells. We analyzed the expression of RPL39 in early-onset PE and normal placental tissues using real-time PCR, western blot analysis, and immunohistochemistry. The results showed that RPL39 was markedly downregulated in early-onset PE placental tissues. RPL39 knockdown inhibited trophoblast cell proliferation, migration, and invasion, as well as placental explant outgrowth. Flow cytometry analysis suggested that knockdown of RPL39 resulted in cell cycle arrest at the G0/G1 phase, but had no significant effect on cell apoptosis. We also found that RPL39 knockdown could alter cell morphology. We then measured the expression of the epithelial cell marker E-cadherin following knockdown of RPL39 in Bewo and HTR8/SVneo cells. RPL39 knockdown increased the expression of E-cadherin. Furthermore, E-cadherin expression was upregulated in placental explant outgrowth tissues transfected with RPL39 small interfering RNA. In conclusion, RPL39 plays an essential role in proliferation, invasion, and migration of trophoblast cells by targeting E-cadherin. Our findings provide novel insight into the mechanisms underlying the occurrence of early-onset PE.
Aberrant activation of the DPAGT1 gene, encoding an essential enzyme in the metabolic pathway of protein N-glycosylation, has been shown to be associated with head and neck squamous cell carcinoma (HNSCC). We have shown that DPAGT1 inhibits intercellular adhesion and functions in a positive feedback loop with Wnt/β-catenin signaling, and that the nuclear β-catenin/CBP signaling underlies the progression of HNSCC to advanced disease. However, the tumor promoting effects of DPAGT1 and its molecular links to the nuclear β-catenin/CBP axis are not well defined. We carried out genomic and functional analyses of DPAGT1 perturbation in indolent (CAL27) and metastatic (HSC-3) HNSCC cells, and in orthotopic HSC-3-derived xenografts in mice. We further generated and annotated DPAGT1 inhibition signature in HSC-3 cells and interrogated it in TCGA HNSCC. We then examined the effects of inhibition of β-catenin-CBP interaction with E7386 on DPAGT1 expression using ChIP-seq and computational approaches. E7386, a novel β-catenin/CBP modulator displays activity profile that closely overlaps with that of ICG-001, but exhibits ~50 - 100-fold lower EC50 values. Ectopic expression of DPAGT1 in indolent CAL27 cells induced epithelial-to-mesenchymal transition (EMT) which coincided with increased abundance of active β-catenin. Partial knockdown of DPAGT1 with siRNA in metastatic HSC-3 cells inhibited EMT, diminished cell migration and enhanced intercellular adhesion. Inhibition of the DPAGT1 enzyme activity using tunicamycin interfered with orthotopic tongue tumor growth and metastasis. DPAGT1 knockdown in HSC-3 cells defined DPAGT1-activated gene signature as enriched in pro-tumorigenic signaling pathways, including stem cell-like genes. Integrative analysis of the DPAGT1-activated genes in TCGA validated the association of DPAGT1 activity with the EMT transcription factors, ZEB1, Twist1/2 and Slug. ChIP-seq analyses without and with the E7386 treatment revealed reduced occupancy of H3K4me3 at two DPAGT1 transcription start sites following the E7386 treatment. In conclusion, our studies align aberrant activation of DPAGT1 with the induction of EMT and stem cell associated genes and suggest a novel role of β-catenin/CBP/MLL1 in the epigenetic regulation DPAGT1 and protein N-glycosylation in HNSCC. Citation Format: Khalid A. Alamoud, Vinay Kartha, Huamei Yang, Andrew Tilston-Lunel, Anthony Federico, Manish Bais, Takachi Owa, Kenichi Nomoto, Xalarabos Varelas, Stefano Monti, Maria A. Kukuruzinska. Identification of a novel role for the β-catenin/CBP signaling in epigenetic regulation of the N-glycosylation gene, DPAGT1, in head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2442.
Head and neck squamous cell carcinoma (HNSCC) is a pernicious malignancy that arises from populations of cancer stem cells (CSCs). We and others have shown that the Wnt/β-catenin signaling pathway drives CSC gene expression mediated, in part, by epigenetic alterations directed by interactions between nuclear β-catenin and the cAMP-responsive element binding (CREB)-binding protein (CBP). In HNSCC, the β-catenin/CBP complex recruits the histone methyltransferase, MLL1, to drive trimethylation of H3K4me3 to induce an open chromatin structure and expression of CSC genes. Further, β-catenin/CBP signaling is highly correlated with the activity of the paralogous transcriptional regulators YAP and TAZ (YAP/TAZ), which are pro-tumorigenic factors in HNSCC. We reported that a small molecule inhibitor of the β-catenin-CBP interaction, ICG-001, blocks oncogenic phenotypes in cellular, zebrafish, and murine models of HNSCC, concomitant with the reduction of CSC traits. Recently, a novel β-catenin/CBP modulator, E7386, has been shown to be effective against a number of neoplasms in preclinical studies. Here, we compared anti-cancer properties of E7386 with ICG-001 to define its molecular mechanisms and validate the β-catenin/CBP axis as a bona fide therapeutic target in HNSCC. Anti-HNSCC activity of E7386 was evaluated in four human HNSCC cell lines using genomic, molecular, biochemical and functional approaches, including global ChIP-seq for H3K4me3. The set of transcripts significantly down-regulated by E7386 in HNSCC cells was projected onto a TCGA RNA-seq data (n=318) using ASSIGN, where samples were scored based on the coordinated expression of the gene signature which, in turn, reflected the level of E7386 inhibition per sample. The E7386 inhibition score was then tested for its association with survival by stratifying TCGA patients (n=318) into high- and low-score groups. Results showed that E7386 had highly overlapping activity signatures with ICG-001 (R = 0.997) with ~50 - 100-fold lower EC50. Similar to ICG-001, treatment with E7386 blocked association between β-catenin and CBP with a concomitant reduction in CBP and MLL1 abundance and global H3K4 trimethylation. E7386 repressed an oncogenic gene expression signature regulated by YAP1/TAZ and impeded HNSCC cell proliferation, promoting E-cadherin adhesion and junctional localization of β-catenin. Importantly, E7386 inhibition-associated transcriptional signatures tracked with tumor grade and poor human HNSCC patient survival. In conclusion, inhibiting β-catenin/CBP activity with E7386 represents a novel approach aimed at targeting epigenetically driven changes in the chromatin structure in HNSCC. Citation Format: Huamei Yang, Vinay Kartha, Khalid A. Alamoud, Anthony Federico, Andrew Tilston-Lunel, Bach-Cuc Nguyen, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Stefano Monti, Maria A. Kukuruzinska. Inhibition of β-catenin/CBP signaling with E7386 targets epigenetic changes associated with cancer stem cells in head and neck cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2453.
Extra-nodal natural killer/T-cell lymphoma, nasal type is a distinct entity of non-Hodgkin's lymphoma. This case report describes a rare presentation of NK/T cell lymphoma on the upper lip. However, lung metastasis was confirmed by CT scans after 2 cycles of chemotherapy. The patient then died of infection and multiple organ failure. This case indicates that Oral Medicine specialists should be aware of this disease, and multiple diagnostic techniques should be applied in order to make an accurate and timely diagnosis.
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