BACKGROUND:Histone lysine demethylase 4B (KDM4B) has been implicated in various pathological processes and human diseases. Glucose metabolism is the main pattern of energy supply in cells and its dysfunction is closely related to tumorigenesis. Recent study shows that KDM4B protects against obesity and metabolic dysfunction. We realized the significant role of KDM4B in metabolism. However, the role of KDM4B in glucose metabolism remains unclear. Here, we sought to delineate the role and mechanism of KDM4B in glucose metabolism in colorectal cancer (CRC).METHODS:We first analyzed the role of KDM4B in glucose uptake and CRC growth. We then investigated the consequences of KDM4B inhibition on the expression of GLUT1 and AKT signaling, also explored the underlying mechanism. Finally, we detected the mechanism in vivo and assessed the potential correlation between the expression of KDM4B and CRC prognosis.RESULTS:We found that KDM4B promoted glucose uptake and ATP production by regulating the expression of GLUT1 via the AKT signaling pathway. KDM4B could interact with TRAF6 and promote TRAF6-mediated ubiquitination of AKT for AKT activation. Furthermore, we demonstrated that KDM4B was overexpressed in CRC specimens and high level of KDM4B was associated with a poor survival rate in CRC patients.CONCLUSIONS:These findings reveal that KDM4B plays an important role in promoting CRC progression by enhancing glucose metabolism.

Objective To explore the role of Hypoxia inducible factor-1 α (HIF-1 α) on the proliferation of the colorectal cancer cells and the mechanism.Methods The expression of histone demethylase 4B (KDM4B) and HIF-1α was detected by Western blotting assay in normoxia and hypoxia;The cell proliferation activity was detected by cell counting kit-8 (CCK-8),and cell cycle was detected by Flow CytoMetry.The data were analyzed by statistical methods (P value less than 0.05 was considered statistically significant).Results The expression of HIF-1α was positively correlated with KDM4B.The Western blotting assay showed that expression of HIF-1α and KDM4B were significant higher in hypoxia model (H) than normoxia(N).CCK-8 showed that A value of siKDM4B group at 24 h (N:0.793 ±0.008,H:0.529 ± 0.021) was significantly different from that of Control Group (N:1.077 ± 0.017,H:0.826 ± 0.019,t =3.452,P ＜ 0.05).At 48 h and 72 h,the A value of the experimental group was lower than control group (P ＜ 0.05).Flow CytoMetry showed that S phase cell proportion of the siKDM4B group (N:40.64％,H:35.50％) was significantly lower than control group (N:56.68％,H:45.64％) (P ＜0.05).Conclusion HIF-1α has a vital role in proliferation activity by regulating KDM4B in colorectal cancer cells.

BACKGROUND:Cellular senescence is a state of irreversible cell growth arrest and senescence cells permanently lose proliferation potential. Induction of cellular senescence might be a novel therapy for cancer cells. TRIB2 has been reported to participate in regulating proliferation and drug resistance of various cancer cells. However, the role of TRIB2 in cellular senescence of colorectal cancer (CRC) and its molecular mechanism remains unclear.METHODS:The expression of TRIB2 in colorectal cancer tissues and adjacent tissues was detected by immunohistochemistry and RT-PCR. The growth, cell cycle distribution and cellular senescence of colorectal cancer cells were evaluated by Cell Counting Kit-8 (CCK8) assay, flow cytometry detection and senescence-associated β-galactosidase staining, respectively. Western blot, RT-PCR and luciferase assay were performed to determine how TRIB2 regulates p21. Immunoprecipitation (IP) and chromatin-immunoprecipitation (ChIP) were used to investigate the molecular mechanisms.RESULTS:We found that TRIB2 expression was elevated in CRC tissues compared to normal adjacent tissues and high TRIB2 expression indicated poor prognosis of CRC patients. Functionally, depletion of TRIB2 inhibited cancer cells proliferation, induced cell cycle arrest and promoted cellular senescence, whereas overexpression of TRIB2 accelerated cell growth, cell cycle progression and blocked cellular senescence. Further studies showed that TRIB2 physically interacted with AP4 and inhibited p21 expression through enhancing transcription activities of AP4. The rescue experiments indicated that silencing of AP4 abrogated the inhibition of cellular senescence induced by TRIB2 overexpression.CONCLUSION:These data demonstrate that TRIB2 suppresses cellular senescence through interaction with AP4 to down-regulate p21 expression. Therefore, TRIB2 could be a potential target for CRC treatment.

Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by the persistent deposition of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Brg1, the core subunit of the SWI/SNF chromatin remodeling complex, has been proved to associated with nonalcoholic steatohepatitis which may progress to cirrhosis. Herein, we determined whether Brg1 regulates liver fibrosis and examined its mechanism by focusing on HSCs activation. In this study, we demonstrate that Brg1 is elevated in human and mouse fibrotic liver tissues and Brg1 mediate the profibrotic response in activated HSCs. Our data indicate that Brg1 regulates the activation of HSCs through TGFβ/Smad signal pathway. Moreover, Brg1 deficiency mice displayed decreased HSCs activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. In addition, Brg1 expression is positively correlated with liver fibrosis in cirrhotic patients and may be a prognostic factor in HCC. Collectively, we demonstrate that Brg1 promotes liver fibrosis by activating HSCs and may represent a potential target for anti-fibrotic therapies.