Risk SNP-induced lncRNA-SLCCl drives colorectal cancer through activating glycolysis signaling

Long non-coding RNAs(lncRNAs)play key roles in colorectal carcinogenesis.Here,we aimed to identify the risk SNP-induced lncRNAs and to investigate their roles in colorectal carcinogenesis.First,we identified rs6695584 as the causative SNP in 1 q41 locus.The A>G mutation of rs6695584 created a protein-binding motif of BATF,altered the enhancer activity,and subsequently activated IncSLCCl expression.Further validation in two independent CRC cohorts confirmed the upregulation of IncSLCCl in CRC tissues,and revealed that increased IncSLCCl expression was associated with poor survival in CRC patients.Mechanistically,lncRNA-SLCCl interacted with AHR and transcriptionally activated HK2 expression,the crucial enzyme in glucose metabolism,thereby driving the glycolysis pathway and accelerating CRC tumor growth.The functional assays revealed that IncSLCCl induced glycolysis activation and tumor growth in CRC mediated by HK2.In addition,HK2 was upregulated in colorectal cancer tissues and positively correlated with IncSLCCl expression and patient survival.Taken together,our findings reveal a risk SNP-mediated oncogene lncRNA-SLCCl promotes CRC through activating the glycolysis pathway.

Epigenetic regulation of hematopoietic stem cell homeostasis

As one of the best characterized adult stem cells,hematopoietic stem cell(HSC)homeostasis is of great importance to hematopoiesis and immunity due to HSC’s abilities of self-renewal and multi-lineage differentiation into functional blood cells.However,excessive self-renewal of HSCs can lead to severe hematopoietic malignancies like leukemia,whereas deficient selfrenewal of HSCs may result in HSC exhaustion and eventually apoptosis of specialized cells,giving rise to abnormalities such as immunodeficiency or anemia.How HSC homeostasis is maintained has been studied for decades and regulatory factors can be generally categorized into two classes:genetic factors and epigenetic factors.Although genetic factors such as signaling pathways or transcription factors have been well explored,recent studies have emerged the indispensable roles of epigenetic factors.In this review,we have summarized regulatory mechanisms of HSC homeostasis by epigenetic factors,including DNA methylation,histone modification,chromatin remodeling,non-coding RNAs,and RNA modification,which will facilitate applications such as HSC ex vivo expansion and exploration of novel therapeutic approaches for many hematological diseases.

SARS-CoV-2 N protein potentiates host NPM1-snoRNA translation machinery to enhance viral replication

Dear Editor,COVID-19(Coronavirus Disease 2019)is causing an unprecedented public health crisis.Protein translation is crucial for virus lifecycle.Nucleocapsid(N)protein is among the most abundant SARS-CoV-2 proteins and highly conserved across coronavirus genus.1 However,its function in subverting host translation machinery is still elusive.

MEK inhibition prevents CAR-T cell exhaustion and differentiation via downregulation of c-Fos and JunB

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T(CAR-T)cells.MEK1/2 inhibitors(MEKIs),widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling,have shown potential synergistic effects when combined with immunotherapy.However,the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial.To address this,we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells.Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation,thereby improving CAR-T cell efficacy against hematological and solid tumors.Remarkably,these effects were independent of the specific scFvs and costimulatory domains utilized in CARs.Mechanistically,analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB.Additionally,the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition.Furthermore,our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion,differentiation,anergy,glycolysis,and apoptosis.In summary,our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation.These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.