NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.

BackgroundCervical cancer (CC), causing significant morbidity and mortality worldwide, is one of the most common gynecological malignancies in women. SFN has been reported as a potential prognostic marker with apparent high expression in tumors. Nevertheless, the function mechanism of SFN is not clear yet in CC.MethodsThe relative expressions of RNAs were detected by real-time quantitative PCR (RT-qPCR). Colony formation assay, EdU stained assay and CCK-8 assay were to check cell proliferation ability in CC. Flow cytometry and apoptosis related proteins analysis were used to measure cells apoptosis capacity. Luciferase reporter assay and RNA pull down assay were to verify the molecular mechanism.ResultsSFN was highly expressed in CC tissues and CC cell lines compared with normal tissues and normal cell line. After interfering SFN, cell proliferation, migration and invasion ability was inhibited as well as cell apoptosis ability was promoted. In subsequence, miR-383-5p exhibited conspicuous low expression in CC tissues. And miR-383-5p was found to bind to SFN and have anti-cancerous effects in CC. Moreover, LINC01128 displayed remarkable high expression in CC tissues. Besides, LINC01128 shortage could reduce the expression of SFN at mRNA and protein levels. And the affinity between LINC01128 and miR-383-5p was verified. In the end, it was proved that LINC01128 could enhance cell proliferation, migration and invasion as well as inhibit cell apoptosis by binding with miR-383-5p and upregulating SFN.ConclusionLINC01128 expedited cells cellular process in CC by binding with miR-383-5p to release SFN.Graphical Abstract

Background Nivolumab plus ipilimumab (N‐I) or pembrolizumab (PEM) is associated with survival improvement as chemotherapy‐free, first‐line treatment for patients with advanced non‐small cell lung carcinoma (NSCLC) and positive programmed cell death ligand 1 (PD‐L1). However, no direct comparison data exist between these two regimens to inform clinical decisions. Therefore, we performed indirect comparison for N‐I versus PEM using frequentist methods. Results Three randomized trials (KEYNOTE‐024, KEYNOTE‐042, and CheckMate 227) involving 2372 patients were included. For patients with tumor PD‐L1 level of ≥1%, pooled meta‐analyses showed that both N‐I and PEM improved overall survival (OS) relative to chemotherapy (N‐I: hazard ratio [HR] 0.82, 95% CI 0.69‐0.97; PEM: HR 0.81, 95% CI 0.71‐0.93); whereas only N‐I significantly improved progression‐free survival (PFS) (N‐I: HR 0.79, 95% CI 0.65‐0.96; PEM: HR 1.07, 95% CI 0.94‐1.21). Neither N‐I nor PEM was associated with improved objective response rate (ORR) compared with chemotherapy (N‐I: relative risk [RR] 1.20, 95% CI 0.98‐1.46; PEM: RR 1.03, 95% CI 0.86‐1.23). Indirect comparisons showed that N‐I was associated with longer PFS than PEM (HR 0.77, 95% CI 0.62‐0.95). However, N‐I was not superior to PEM in terms of OS (HR 0.98, 95% CI 0.77‐1.24) and ORR (RR 1.17, 95% CI 0.89‐1.52). N‐I showed a less favorable toxicity profile relative to PEM (all grade adverse events: RR 1.28, 95% CI 1.17‐1.40). Conclusions N‐I and PEM provide comparable OS benefit for PD‐L1‐positive NSCLC. N‐I further improves PFS relative to PEM but at meaningful cost of toxicities.

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Purpose: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML.Experimental Design: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model.Results: Six flow cytometry-validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P ¼ 0.041), 44% versus 24% (P ¼ 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P ¼ 0.005), 2.12 (P ¼ 0.004), 2.02 (P ¼ 0.034), 1.66 (P ¼ 0.019), and 1.59 (P ¼ 0.001) in the training and validation cohorts, respectively.Conclusions: Our immune risk score complements current AML prediction models.