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Background Extranodal natural killer/T-cell lymphoma (NKTL) is an aggressive type of non-Hodgkin lymphoma with dismal outcome. A better understanding of disease biology and key oncogenic process is necessary for the development of targeted therapy. Super-enhancers (SEs) have been shown to drive pivotal oncogenes in various malignancies. However, the landscape of SEs and SE-associated oncogenes remain elusive in NKTL. Methods We used Nano-ChIP-seq of the active enhancer marker histone H3 lysine 27 acetylation (H3K27ac) to profile unique SEs NKTL primary tumor samples. Integrative analysis of RNA-seq and survival data further pinned down high value, novel SE oncogenes. We utilized shRNA knockdown, CRISPR-dCas9, luciferase reporter assay, ChIP-PCR to investigate the regulation of transcription factor (TF) on SE oncogenes. Multi-color immunofluorescence (mIF) staining was performed on an independent cohort of clinical samples. Various function experiments were performed to evaluate the effects of TOX2 on the malignancy of NKTL in vitro and in vivo. Results SE landscape was substantially different in NKTL samples in comparison with normal tonsils. Several SEs at key transcriptional factor (TF) genes, including TOX2, TBX21(T-bet), EOMES, RUNX2, and ID2, were identified. We confirmed that TOX2 was aberrantly overexpressed in NKTL relative to normal NK cells and high expression of TOX2 was associated with worse survival. Modulation of TOX2 expression by shRNA, CRISPR-dCas9 interference of SE function impacted on cell proliferation, survival and colony formation ability of NKTL cells. Mechanistically, we found that RUNX3 regulates TOX2 transcription by binding to the active elements of its SE. Silencing TOX2 also impaired tumor formation of NKTL cells in vivo. Metastasis-associated phosphatase PRL-3 has been identified and validated as a key downstream effector of TOX2-mediated oncogenesis. Conclusions Our integrative SE profiling strategy revealed the landscape of SEs, novel targets and insights into molecular pathogenesis of NKTL. The RUNX3-TOX2-SE-TOX2-PRL-3 regulatory pathway may represent a hallmark of NKTL biology. Targeting TOX2 could be a valuable therapeutic intervene for NKTL patients and warrants further study in clinic.

Triple-negative breast cancer is still a difficult point in clinical treatment at present, and a deep study of its pathogenesis has great clinical value. Therefore, our research mainly focuses on exploring the progression of triple-negative breast cancer and determines the important role of the HJURP/YAP1/NDRG1 transcriptional regulation axis in triple-negative breast cancer. We observed significantly increased HJURP expression levels in triple-negative breast cancer compared to other subtypes. HJURP could affect the level of ubiquitination modification of YAP1 protein and then regulate its downstream transcriptional activity. Mechanistically, we found that YAP1 positively regulates NDRG1 transcription by binding the promoter region of the NDRG1 gene. And HJURP/YAP1/NDRG1 axis could affect cell proliferation and chemotherapy sensitivity in triple-negative breast cancer. Taken together, these findings provide insights into the transcriptional regulation axis of HJURP/YAP1/NDRG1 in triple-negative breast cancer progression and therapeutic response.

Background The ability to use dissolved organic phosphorus (DOP) is important for survival and competition when phytoplankton are faced with scarcity of dissolved inorganic phosphorus (DIP). However, phosphorus availability to the freshwater dinoflagellate Peridinium bipes has received relatively little attention, the efficiency of glycerol phosphate use by phytoplankton has rarely been investigated, and the regulatory molecular mechanisms remain unclear. Result In the present study, cultures of the freshwater dinoflagellate Peridinium bipes were set up in 119 medium (+DIP), DIP-depleted 119 medium (P-free), and β-glycerol phosphate-replacing-DIP medium (+DOP). Gene expression was analyzed using transcriptomic sequencing. The growth rate of cells in DOP treatment group was similar to that in DIP group, but chlorophyll a fluorescence parameters RC/CS0, ABS/CS0, TR0/CS0, ET0/CS0 and RE0/CS0 markedly decreased in the DOP group. Transcriptomic analysis revealed that genes involved in photosynthesis, including psbA, psbB, psbC, psbD, psaA and psaB, were downregulated in the DOP group relative to the DIP group. Glycerol-3-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase, rather than alkaline phosphatase, were responsible for β-glycerol phosphate use. Intercellular gluconeogenesis metabolism was markedly changed in the DOP group. In addition, genes involved in ATP synthases, the TCA cycle, oxidative phosphorylation, fatty acid metabolism and amino acid metabolism in P. bipes were significantly upregulated in the DOP group compared with the DIP treatment. Conclusions These findings suggested that β-glycerol phosphate could influence the photosynthesis and metabolism of P. bipes, which provided a comprehensive understanding of the phosphorus physiology of P. bipes. The mechanisms underlying the use of β-glycerol phosphate and other DOPs are different in different species of dinoflagellates and other phytoplankton. DIP reduction may be more effective in controlling the bloom of P. bipes than DOP reduction.

The APOE ε4 allele is associated with impaired intrinsic functional connectivity in neural networks, especially in the default mode network (DMN). However, effective connectivity (EC) reflects the direct causal effects of one brain region to another, which has rarely been investigated. Recently, Granger causality analysis (GCA) proved suitable for the study of directionality in neuronal interactions. Using GCA, we examined the differences in the EC between the anterior medial prefrontal cortex/posterior cingulate cortex (aMPFC/PCC) and the whole brain in 17 ε4 carrying and 32 non-carrying cognitively intact elderly individuals. Furthermore, correlation analyses were performed between the abnormal EC and cognition/neuropathological indices. Compared with the non-carriers, the results showed that the ε4 carriers exhibited decreased EC from the PCC to the whole brain in the middle temporal gyrus (MTG), the anterior cingulate cortex (ACC), and the precuneus (PCu). Meanwhile, the ε4 carriers demonstrated increased EC from the whole brain to the aMPFC in the inferior parietal lobe (IPL) and the postcentral gyrus (PCG). The correlation analyses suggested that the EC from the IPL/PCG to the aMPFC was related to episodic memory in non-carriers, while the decreased EC from the PCC to the ACC was associated with increased levels of t-tau in the ε4 carriers. In ε4 carriers, a negative influence can be traced from the PCC to both the anterior and posterior DMN subsystems; meanwhile, the anterior DMN subsystem receives compensatory effects from the parietal cortex. Early increases in AD-related pathologies in the PCC may act as first factors during this pathological process.

Background Sensitivity differences to chemical pollutants in different phytoplankton species may potentially shape the community structure of phytoplankton. However, detailed information supporting the understanding of sensitivity variations between phytoplankton species is still limited. Results To investigate sensitivity differences between the cyanobacterium Microcystis aeruginosa, and the green alga Chlorella sp. to paraquat, multiple physiological parameters were measured and compared through acute and chronic toxicity assays. Early photosynthetic responses during acute toxicity assays showed that paraquat affects Photosynthesis System II energy fluxes in M. aeruginosa within 3 h of exposure, but not in Chlorella sp. After 5 h of cumulative exposure, an EC50 based on the maximum quantum yield for primary photochemistry of 0.54 mg L−1 was achieved and remained more or less constant, while the EC50 values for Chlorella fluctuated around 44.76 ± 3.13 mg L−1 after 24 h of exposure. During chronic 96 h exposure to paraquat, differences in antioxidant enzyme activities, reactive oxygen species (ROS) levels, and ultrastructure were observed in both M. aeruginosa and Chlorella sp. An increase in the intracellular levels of ROS and the number of plasma membrane damaged cells was observed in M. aeruginosa in the 0.2, 0.5, and 1.0 mg L−1 treatments (p Chlorella. In addition, at an exposure level of 1.0 mg L−1, extensive disruption of cell structure was observed in M. aeruginosa. Conversely, little disarrangement of organelle structure was found in Chlorella sp. Conclusion These results confirm that paraquat is more toxic to M. aeruginosa than to Chlorella sp. The sensitivity differences between these two species (one a prokaryote and the other a eukaryote) to paraquat might be partially explained by the differences in cell structure (cell wall and photosynthetic structure), the enzymatic antioxidant system, and the physiological vulnerability. The multiple physiological endpoint analysis approach used in the current study provides more detailed information for understanding the mechanisms of sensitivity variation between these phytoplankton species.

Background Tamoxifen resistance remains a clinical challenge for hormone receptor-positive breast cancer. Recently, dysregulations in autophagy have been suggested as a potential mechanism for tamoxifen resistance. Although the long noncoding RNA H19 is involved in various stages of tumorigenesis, its role in tamoxifen resistance remains unknown. Here, we assessed the role of H19 in the development of tamoxifen-resistant breast cancer. Methods Quantitative real-time PCR analyzed expression of H19 in tamoxifen-resistant breast cancer tissues. Knockdown of H19 was used to assess the sensitivity to tamoxifen in vitro and in vivo. Both knockdown and overexpression of H19 were used to analyze the status of autophagy. Real-time quantitative methylation-specific polymerase chain reaction, chromatin immunoprecipitation, immunofluorescence, and Western blot were used to explore the tamoxifen resistance mechanism of H19. Results In this study, we observed that the expression of H19 was substantially upregulated in tamoxifen-resistant breast cancer cell line and tumor tissues, and knockdown of H19 enhanced the sensitivity to tamoxifen both in vitro and in vivo. Furthermore, knockdown of H19 significantly inhibited autophagy in MCF7 tamoxifen-resistant (MCF7/TAMR) cells. Conversely, overexpression of H19 promoted autophagy. Interestingly, overexpression of H19 in MCF7 tamoxifen-sensitive cells could recapitulate tamoxifen resistance. Moreover, an increase in methylation in the promoter region of Beclin1 was observed in MCF7/TAMR-shH19 cells. In the double knockdown groups, both shH19+shSAHH and shH19+shDNMT3B rescued the Beclin1 promoter region methylation levels and reactivated autophagy functions. A chromatin immunoprecipitation assay further validated that DNMT3B binds to the Beclin1 promoter region and the knockdown of H19 increases this binding. Conclusions Our findings demonstrate that H19 induces autophagy activation via the H19/SAHH/DNMT3B axis, which could contribute to tamoxifen resistance in breast cancer. Electronic supplementary material The online version of this article (10.1186/s13045-019-0747-0) contains supplementary material, which is available to authorized users.

Accumulating evidence suggests that placenta-specific 8 (PLAC8) plays an important role in normal cellular process and human diseases, including multiple types of human tumors, and its role is highly relied upon in cellular and physiologic contexts. However, there are no reports on its expression profile and biological roles during lung cancer development. In the current study, both the clinical implications and biological effects of PLAC8 in lung cancer (LC) progression were investigated, and we identified and described the novel Krüppel-like factor 4 (KLF4)/PLAC8 regulatory pathway in cancer progression. Elevated PLAC8 levels were positively correlated with tumor size, histological grade, and tumor node metasis (TNM) stage, and LC patients with high PLAC8 expression suffered poor outcomes. In vitro and in vivo assays further revealed that endogenous PLAC8 promoted cell proliferation and tumor formation. We also found downregulated PLAC8 protein in several LC cell lines following the induction of KLF4, and immunohistochemistry analysis of LC tissues by microarray indicated a potential inverse correlation between PLAC8 and KLF4 expression. Luciferase reporter analysis and chromatin immunoprecipitation assays determined that KLF4 negatively regulated PLAC8 promoter activity via directly binding to the promoter region. Furthermore, the growth inhibition resulting from KLF4 overexpression was partially rescued by ectopic PLAC8 expression. Together, our data uncovered a previously unidentified role of PLAC8 as a central mediator in LC progression. PLAC8 was transcriptionally repressed by KLF4, and the novel KLF4/PLAC8 axis may act as a promising candidate target for LC diagnosis and therapy.