Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers

Designer carbon nanotubes for contaminant removal in water and wastewater: A critical review

The search for effective materials for environmental cleanup is a scientific and technological issue of paramount importance. Among various materials, carbon nanotubes (CNTs) possess unique physicochemical, electrical, and mechanical properties that make them suitable for potential applications as environmental adsorbents, sensors, membranes, and catalysts. Depending on the intended application and the chemical nature of the target contaminants, CNTs can be designed through specific functionalization or modification processes. Designer CNTs can remarkably enhance contaminant removal efficiency and facilitate nanomaterial recovery and regeneration. An increasing number of CNT-based materials have been used to treat diverse organic, inorganic, and biological contaminants. These success stories demonstrate their strong potential in practical applications, including wastewater purification and desalination. However, CNT-based technologies have not been broadly accepted for commercial use due to their prohibitive cost and the complex interactions of CNTs with other abiotic and biotic environmental components. This paper presents a critical review of the existing literature on the interaction of various contaminants with CNTs in water and soil environments. The preparation methods of various designer CNTs (surface functionalized and/or modified) and the functional relationships between their physicochemical characteristics and environmental uses are discussed. This review will also help to identify the research gaps that must be addressed for enhancing the commercial acceptance of CNTs in the environmental remediation industry

Targeting HER2 beyond breast cancer

The structural basis of blocking human epidermal growth factor receptor-2 (HER2) dimerization remains of great interest to generate effective anti-cancer therapies. Despite clinically feasible outcome in mammary tumors, a fine consensus between efficacy and safety remains a critical challenge beyond breast cancer. Here we extrapolate on the balancing act using recently reported clinical findings in salivary ductal carcinomas

Targeting HER2 beyond breast cancer.

The structural basis of blocking human epidermal growth factor receptor-2 (HER2) dimerization remains of great interest to generate effective anti-cancer therapies. Despite clinically feasible outcome in mammary tumors, a fine consensus between efficacy and safety remains a critical challenge beyond breast cancer. Here we extrapolate on the balancing act using recently reported clinical findings in salivary ductal carcinomas

Novel molecular players of X chromosome inactivation: new technologies and new insights

The dosage compensation in placental mammals is achieved by silencing of one copy of the X chromosomes in a female cell by a process called X chromosome inactivation (XCI). XCI ensures equal gene dosage for X-linked genes between the two genders. Although the choice of X chromosome to be silenced is random, once the silencing of the X chromosome has been established, this process is highly regulated and maintained throughout subsequent cell divisions. A long non-coding RNA, Xist, and its interacting proteins execute this multistep process, but several of these regulatory proteins remain unidentified. Recent technological advances based on the genetic and proteomics screening have identified several new regulatory factors as well as dissected the molecular details of XCI regulation. Moreover, identification of regulators of XCI offers an opportunity to explore reactivation of the inactive X chromosome (Xi) as a potential therapeutic strategy to treat X-linked diseases, like Rett syndrome. Here, we summarize recent reports that identified new regulatory proteins and RNA species playing a crucial role in Xist localization and spreading, recruitment of silencing machinery to the Xi, Xist interaction with chromatin, and structural organization of the Xi in the nuclei

Genetic and pharmacological reactivation of the mammalian inactive X chromosome

X-chromosome inactivation (XCI), the random transcriptional silencing of one X chromosome in somatic cells of female mammals, is a mechanism that ensures equal expression of X-linked genes in both sexes. XCI is initiated in cis by the noncoding Xist RNA, which coats the inactive X chromosome (Xi) from which it is produced. However, trans-acting factors that mediate XCI remain largely unknown. Here, we perform a large-scale RNA interference screen to identify trans-acting XCI factors (XCIFs) that comprise regulators of cell signaling and transcription, including the DNA methyltransferase, DNMT1. The expression pattern of the XCIFs explains the selective onset of XCI following differentiation. The XCIFs function, at least in part, by promoting expression and/or localization of Xist to the Xi. Surprisingly, we find that DNMT1, which is generally a transcriptional repressor, is an activator of Xist transcription. Small-molecule inhibitors of two of the XCIFs can reversibly reactivate the Xi, which has implications for treatment of Rett syndrome and other dominant X-linked diseases. A homozygous mouse knockout of one of the XCIFs, stanniocalcin 1 (STC1), has an expected XCI defect but surprisingly is phenotypically normal. Remarkably, X-linked genes are not overexpressed in female Stc1(-/-) mice, revealing the existence of a mechanism(s) that can compensate for a persistent XCI deficiency to regulate X-linked gene expression