Mechanistic and functional extrapolation of SET and MYND domain-containing protein 2 to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal neoplasms worldwide and represents the vast majority of pancreatic cancer cases. Understanding the molecular pathogenesis and the underlying mechanisms involved in the initiation, maintenance, and progression of PDAC is an urgent need, which may lead to the development of novel therapeutic strategies against this deadly cancer. Here, we review the role of SET and MYND domain-containing protein 2 (SMYD2) in initiating and maintaining PDAC development through methylating multiple tumor suppressors and oncogenic proteins. Given the broad substrate specificity of SMYD2 and its involvement in diverse oncogenic signaling pathways in many other cancers, the mechanistic extrapolation of SMYD2 from these cancers to PDAC may allow for developing new hypotheses about the mechanisms driving PDAC tumor growth and metastasis, supporting a proposition that targeting SMYD2 could be a powerful strategy for the prevention and treatment of PDAC.

Unique SMYD5 Structure Revealed by AlphaFold Correlates with Its Functional Divergence.

SMYD5 belongs to a special class of protein lysine methyltransferases with an MYND (Myeloid-Nervy-DEAF1) domain inserted into a SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) domain. Despite recent advances in its functional characterization, the lack of the crystal structure has hindered our understanding of the structure-and-function relationships of this most unique member of the SMYD protein family. Here, we demonstrate the reliability of using AlphaFold structures for understanding the structure and function of SMYD5 by comparing the AlphaFold structures to the known crystal structures of SMYD proteins, using an inter-residue distance maps-based metric. We found that the AlphaFold confidence scores are inversely associated with the refined B-factors and can serve as a structural indicator of conformational flexibility. We also found that the N-terminal sequence of SMYD5, predicted to be a mitochondrial targeting signal, contains a novel non-classical nuclear localization signal. This sequence is structurally flexible and does not have a well-defined conformation, which might facilitate its recognition for SMYD5's cytonuclear transport. The structure of SMYD5 is unique in many aspects. The "crab"-like structure with a large negatively charged cleft provides a potential binding site for basic molecules such as protamines. The less positively charged MYND domain is associated with the undetectable DNA-binding ability. The most surprising feature is an incomplete target lysine access channel that lacks the evolutionarily conserved tri-aromatic arrangement, being associated with the low H3/H4 catalytic activity. This study expands our understanding of the SMYD protein family from a classical two-lobed structure to a structure of its own kind, being as a fundamental determinant of its functional divergence.

ERK3 is transcriptionally upregulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in non-melanoma skin cancers.

BACKGROUND: p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. ∆Np63α is the main isoform of p63 and highly expressed in Non-melanoma skin cancer (NMSC). Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose biochemical features and cellular regulation are distinct from those of conventional MAPKs such as ERK1/2. While ERK3 has been shown to be upregulated in lung cancers and head and neck cancers, in which it promotes cancer cell migration and invasion, little is known about the implication of ERK3 in NMSCs. METHODS: Fluorescent immunohistochemistry was performed to evaluate the expression levels of ΔNp63α and ERK3 in normal and NMSC specimens. Dunnett's test was performed to compare mean fluorescence intensity (MFI, indicator of expression levels) of p63 or ERK3 between normal cutaneous samples and NMSC samples. A mixed effects (ANOVA) test was used to determine the correlation between ΔNp63α and ERK3 expression levels (MFI). The regulation of ERK3 by ΔNp63α was studied by qRT-PCR, Western blot and luciferase assay. The effect of ERK3 regulation by ΔNp63α on cell migration was measured by performing trans-well migration assay. RESULTS: The expression level of ∆Np63α is upregulated in NMSCs compared to normal tissue. ERK3 level is significantly upregulated in AK and SCC in comparison to normal tissue and there is a strong positive correlation between ∆Np63α and ERK3 expression in normal skin and skin specimens of patients with AK, SCC or BCC. Further, we found that ∆Np63α positively regulates ERK3 transcript and protein levels in A431 and HaCaT skin cells, underlying the upregulation of ERK3 expression and its positive correlation with ∆Np63α in NMSCs. Moreover, similar to the effect of ∆Np63α depletion, silencing ERK3 greatly enhanced A431 cell migration. Restoration of ERK3 expression under the condition of silencing ∆Np63α counteracted the increase in cell migration induced by the depletion of ∆Np63α. Mechanistically, ERK3 inhibits the phosphorylation of Rac1 G-protein and the formation of filopodia of A431 skin SCC cells. CONCLUSIONS: ERK3 is positively regulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in NMSC.

Knowledge and Perceptions of Common Breast Cancer Risk Factors in Northern Saudi Arabia

Background: Breast cancer is the second leading cause of cancer death in women around the world. The degree of adoption of a preventive lifestyle offers valuable information for planning appropriate intervention programs for improving women's health. The objective of the present study was to assess the levels of breast cancer related knowledge among a Northern Saudi population. Methodology: In this cross sectional study, data were obtained from 566 Saudi volunteers living in the city of Hail, the Kingdom of Saudi Arabia (KSA). Results: With regard to breast cancer risk factors, 427/566 (75.4%) of participants answered in the affirmative to whether breast cancer could be inherited. For early puberty and late menopause, 209/566 (37%) were in agreement with increased risk, for low and delayed child birth, 261/566 (46%), and for overweight and obesity, 210/566(37%). For the question of whether natural breast feeding can reduce the risk of breast cancer, only 35/566 (6.2%) said yes. Conclusion: There is a general lack of knowledge regarding several BC risk factors among the northern Saudi community which necessitates urgent implementation of educational programs.