USF2 promotes autophagy and proliferation in chronic lymphocytic leukemia by inhibiting STUB1-induced NFAT5 ubiquitination.

Chronic lymphocytic leukemia (CLL) mainly affects the health of older adults and is difficult to cure. Upstream stimulatory factor 2 (USF2) has been implicated in several diseases and conditions including cancers. However, the effect of USF2 on CLL has not been elucidated. To investigate the effect of USP2 on proliferation and autophagy of CLL, and to explore the underlying mechanism. The mRNA of USF2 and STIP1 homology and U-Box containing protein 1 (STUB1) was analyzed using qRT-PCR. Western blots were used to evaluate the expression level of USF2, LC3II, Beclin-1, P62, STUB1, and NFAT5. The cell proliferation was evaluated using CCK-8 and EdU assays. The cell apoptosis was evaluated using flow cytometry. Indirect fluorescent assay (IFA) was performed to analyze LC3 signal. Nuclear factor of activated T-cells 5 (NFAT5) ubiquitination was detected using immunoprecipitation (IP) assay. The CLL progression was evaluated in xenotransplantation model of nude mice. USF2 was highly expressed in CLL tissues and cell lines. USF2 knockdown suppressed the cell viability and EdU incorporation, while promoting cell apoptosis. Meanwhile, USF2 knockdown reduced the level of LC3II and Beclin-1, but increased P62, illustrating USF2 knockdown inhibiting autophagy. USF2 induced NFAT5 ubiquitination and promoted NFAT5 protein level via repressing STUB1. The downregulation of USF2 weakened CLL progression in xenotransplantation model of nude mice. CLL survival and autophagy was dependent on highly expressed USF2 which promoted the expression and ubiquitination of NFAT5 through inhibiting the transcription of STUB1, which makes USF2 a promising therapeutic candidate for CLL treatment.

NFAT5 Regulated by STUB1, Facilitates Malignant Cell Survival and p38 MAPK Activation by Upregulating AQP5 in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a clonal proliferative disease of mature B lymphocytes. To further improve the prognosis of patients, it is necessary to further elucidate the pathogenesis of CLL and find more effective therapeutic targets. Nuclear Factor of Activated T cells 5 (NFAT5) is the major activated transcription factor (TF) upon osmotic pressure increase in mammalian cells, and it also regulates many target genes to affect various cellular functions. The effects of NFAT5 on tumor growth and metastasis have also been widely revealed. However, the effects of NFAT5 on the progression of CLL are still unclear. In this study, we found abnormally high expression of NFAT5 in human CLL patients. Additionally, NFAT5 depletion suppressed proliferation and stimulated apoptosis of CLL cells. Our data further confirmed NFAT5 regulated AQP5 expression and the phosphorylation of p38 MAPK. We also found that AQP5 overexpression reversed the inhibitory effect of NFAT5 depletion on cell proliferation in CLL cells. Furthermore, we revealed STUB1 directly bound to NFAT5 and promoted its degradation. Taken together, our results indicate the involvement of NFAT5 in CLL progression and suggest that NFAT5 could serve as a promising therapeutic target for CLL treatment.

Long non-coding RNA LINC01268 promotes cell growth and inhibits cell apoptosis by modulating miR-217/SOS1 axis in acute myeloid leukemia.

The aim of this study was to evaluate the pathogenic role of newly identified long non-coding (lnc)-RNA LINCO1268 in acute myeloid leukemia (AML), and investigate its therapeutic potential. The expression level of LINC01268 in AML was measured by quantitative PCR (qPCR). The viability, cell cycle progression, and apoptosis of AML cells were measured by CCK-8 assay and flow cytometry, respectively. The interaction between LINC01268 and miR-217 were predicted by the miRDB website, and then verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The relationship between miR-217 and SOS1 was predicted by TargetScan website, and verified by luciferase reporter assay. LINC01268 was significantly upregulated by 1.6 fold in bone marrow samples of AML patients, which was associated with poor prognosis. LINC01268 was also significantly upregulated in AML cells. LINC01268 knockdown inhibited viability and cell cycle progression but promoted apoptosis of AML cells. Furthermore, LINC01268 functioned as a ceRNA via competitively binding to miR-217, and SOS1 was identified as a target of miR-217. Moreover, LINC01268 positively regulated SOS1 expression to promote AML cell viability and cell cycle progression but inhibited apoptosis via sponging miR-217. LINC01268 promoted cell growth and inhibited cell apoptosis through modulating miR-217/SOS1 axis in AML. This study offers a novel molecular mechanism for a better understanding of the pathology of AML. LINC01268 could be considered as a potential biomarker for the therapy and diagnosis of AML.

Long non-coding RNA LINC01268 promotes cell growth and inhibits cell apoptosis by modulating miR-217/SOS1 axis in acute myeloid leukemia

The aim of this study was to evaluate the pathogenic role of newly identified long non-coding (lnc)-RNA LINCO1268 in acute myeloid leukemia (AML), and investigate its therapeutic potential. The expression level of LINC01268 in AML was measured by quantitative PCR (qPCR). The viability, cell cycle progression, and apoptosis of AML cells were measured by CCK-8 assay and flow cytometry, respectively. The interaction between LINC01268 and miR-217 were predicted by the miRDB website, and then verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. The relationship between miR-217 and SOS1 was predicted by TargetScan website, and verified by luciferase reporter assay. LINC01268 was significantly upregulated by 1.6 fold in bone marrow samples of AML patients, which was associated with poor prognosis. LINC01268 was also significantly upregulated in AML cells. LINC01268 knockdown inhibited viability and cell cycle progression but promoted apoptosis of AML cells. Furthermore, LINC01268 functioned as a ceRNA via competitively binding to miR-217, and SOS1 was identified as a target of miR-217. Moreover, LINC01268 positively regulated SOS1 expression to promote AML cell viability and cell cycle progression but inhibited apoptosis via sponging miR-217. LINC01268 promoted cell growth and inhibited cell apoptosis through modulating miR-217/SOS1 axis in AML. This study offers a novel molecular mechanism for a better understanding of the pathology of AML. LINC01268 could be considered as a potential biomarker for the therapy and diagnosis of AML.