Runx3/Pebp2alphaC null mouse gastric mucosa exhibits hyperplasias due to stimulated proliferation and suppressed apoptosis in epithelial cells, and the cells are resistant to growth-inhibitory and apoptosis-inducing action of TGF-beta, indicating that Runx3 is a major growth regulator of gastric epithelial cells. Between 45% and 60% of human gastric cancer cells do not significantly express RUNX3 due to hemizygous deletion and hypermethylation of the RUNX3 promoter region. Tumorigenicity of human gastric cancer cell lines in nude mice was inversely related to their level of RUNX3 expression, and a mutation (R122C) occurring within the conserved Runt domain abolished the tumor-suppressive effect of RUNX3, suggesting that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer.

Inactivation of tumor suppressor Runt-related transcription factor 3 (RUNX3) plays an important role during early tumorigenesis. However, posttranslational modifications (PTM)-based mechanism for the inactivation of RUNX3 under hypoxia is still not fully understood. Here, we demonstrate a mechanism that G9a, lysine-specific methyltransferase (KMT), modulates RUNX3 through PTM under hypoxia. Hypoxia significantly increased G9a protein level and G9a interacted with RUNX3 Runt domain, which led to increased methylation of RUNX3 at K129 and K171. This methylation inactivated transactivation activity of RUNX3 by reducing interactions with CBFβ and p300 cofactors, as well as reducing acetylation of RUNX3 by p300, which is involved in nucleocytoplasmic transport by importin-α1. G9a-mediated methylation of RUNX3 under hypoxia promotes cancer cell proliferation by increasing cell cycle or cell division, while suppresses immune response and apoptosis, thereby promoting tumor growth during early tumorigenesis. Our results demonstrate the molecular mechanism of RUNX3 inactivation by G9a-mediated methylation for cell proliferation and antiapoptosis under hypoxia, which can be a therapeutic or preventive target to control tumor growth during early tumorigenesis.

The shortage and uneven spatial and distribution of agricultural water resources has greatly restricted the sustainable development of regional society and economy. In this study, an improved five-element connection number set pair analysis model, which subdivides the same–different–opposite connection number in the set pair analysis theory to enhance the integrity and effectiveness of the original ternary connection numbers is constructed to evaluate the agricultural water resources carrying capacity (AWRCC) in the Haihe River Basin. Based on this evaluation result, an optimization model (AROL model) is proposed to optimize the effective irrigation area and groundwater exploitation to achieve a “better level” of AWRCC. The evaluation result shows that the current AWRCC of the Haihe River Basin is relatively low. The AWRCC in Shanxi, Inner Mongolia, and Liaoning is Level III and the current agricultural water resources are not overloaded but have little carrying potential. The AWRCC of Beijing, Tianjin, Hebei, Henan, and Shandong are rated IV and overloaded, among which Shandong has the lowest comprehensive score and the most serious overload. The optimization result shows that the extraction and conservation of groundwater in most areas of the Haihe River Basin is unbalanced and the effective irrigation area needs to be increased. With different current conditions in different areas, the groundwater exploitation and the effective irrigation area is adjusted correspondingly. Among the areas, the adjustment of groundwater exploitation and the effective irrigation area in Hebei are the most significant.

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