Sequencing studies have implicated haploinsufficiency of ARID1B, a SWI/SNF chromatin-remodeling subunit, in short stature (Yu et al., 2015), autism spectrum disorder (O'Roak et al., 2012), intellectual disability (Deciphering Developmental Disorders Study, 2015), and corpus callosum agenesis (Halgren et al., 2012). In addition, ARID1B is the most common cause of Coffin-Siris syndrome, a developmental delay syndrome characterized by some of the above abnormalities (Santen et al., 2012; Tsurusaki et al., 2012; Wieczorek et al., 2013). We generated Arid1b heterozygous mice, which showed social behavior impairment, altered vocalization, anxiety-like behavior, neuroanatomical abnormalities, and growth impairment. In the brain, Arid1b haploinsufficiency resulted in changes in the expression of SWI/SNF-regulated genes implicated in neuropsychiatric disorders. A focus on reversible mechanisms identified Insulin-like growth factor (IGF1) deficiency with inadequate compensation by Growth hormone-releasing hormone (GHRH) and Growth hormone (GH), underappreciated findings in ARID1B patients. Therapeutically, GH supplementation was able to correct growth retardation and muscle weakness. This model functionally validates the involvement of ARID1B in human disorders, and allows mechanistic dissection of neurodevelopmental diseases linked to chromatin-remodeling.DOI: http://dx.doi.org/10.7554/eLife.25730.001
Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor ) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress through copy number alterations, and expression correlates with prognosis in Wilms tumors. overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, transactivates (), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.
TASIN (Truncated APC-Selective Inhibitors) compounds are selectively toxic to colorectal cancer cells with APC mutations, although their mechanism of action remains unknown. Here, we found that TASINs inhibit three enzymes in the postsqualene cholesterol biosynthetic pathway including EBP, DHCR7, and DHCR24. Even though all three of these enzymes are required for cholesterol biosynthesis, only inhibition of the most upstream enzyme, EBP, led to cancer cell death via depletion of downstream sterols, an observation that was confirmed by genetic silencing of EBP. Pharmacologic inhibition or genetic silencing of either DHCR7 or DHCR24 had no impact on cell viability. By using photoaffinity probes to generate a relationship between chemical structure and probe competition, we identified compounds that selectively inhibit either EBP or DHCR7. These studies identify EBP, but not downstream enzymes in the cholesterol biosynthetic pathway, as a target in APC mutant colorectal cancer and also have implications for the clinical development of highly selective EBP inhibitors.
Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells and is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. .
Background: Wilms tumor and rhabdoid tumor can have similar clinical presentations, but they have distinct histological and biological features. For instance, Wilms tumors commonly bear mutations in kidney differentiation or microRNA processing genes, whereas rhabdoid tumor is characterized by loss of SMARCB1. Aims:We initially set out to characterize and identify tumor suppressor microRNAs in WT-CLS1, which had been described as a Wilms tumor cell line. Methods and Results:We characterized the cell line WT-CLS1 by whole exome sequencing, RNA-seq, and xenograft histology. We measured the effect of microRNA overexpression on WiT49, WT-CLS1, BT-12, and CHLA-06-ATRT.We found that miR-16 significantly impairs cell proliferation in WT-CLS1 by repressing numerous cell cycle genes, including the D-type cyclins. In addition, we found that the WT-CLS1 cell line demonstrates the classic histological, mutational, and transcriptional hallmarks of rhabdoid tumor, including SMARCB1 loss. Lastly, miR-16 also represses cell cycle genes and impairs proliferation in the BT-12 and CHLA-06-ATRT rhabdoid tumor cell lines. Conclusions:The loss of SMARCB1 warrants reclassification of WT-CLS1 as rhabdoid tumor. Overexpression of miR-16 significantly abrogates proliferation of WT-CLS1 and other rhabdoid tumor cell lines. Further studies are necessary to gain insight into the potential for miR-16 to be a tumor suppressor or a novel therapeutic in rhabdoid tumor. KEYWORDS miR-16, rhabdoid tumor, WT-CLS1Abbreviations: ATRT, atypical teratoid/rhabdoid tumor; CDK4, cyclin-dependent kinase 4; EZH2, Enhancer of zeste homolog 2; miRNA, microRNA; SWI/SNF, Switch/ sucrose non-fermentable
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