Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling in melanoma phenotype switching

In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFβ/SMAD, Hippo/YAP/TAZ, and Wnt/β-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFβ/SMAD, YAP/TAZ, and β-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of β-catenin, with YAP/TAZ governing an essential subprogram of TGFβ-induced phenotype switching. Wnt/β-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ–induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

Set4 regulates stress response genes and coordinates histone deacetylases within yeast subtelomeres

The yeast chromatin protein Set4 is a member of the Set3-subfamily of SET domain proteins which play critical roles in the regulation of gene expression in diverse developmental and environmental contexts. We previously reported that Set4 promotes survival during oxidative stress and regulates expression of stress response genes via stress-dependent chromatin localization. In this study, global gene expression analysis and investigation of histone modification status identified a role for Set4 in maintaining gene repressive mechanisms within yeast subtelomeres under both normal and stress conditions. We show that Set4 works in a partially overlapping pathway to the SIR complex and the histone deacetylase Rpd3 to maintain proper levels of histone acetylation and expression of stress response genes encoded in subtelomeres. This role for Set4 is particularly critical for cells under hypoxic conditions, where the loss of Set4 decreases cell fitness and cell wall integrity. These findings uncover a new regulator of subtelomeric chromatin that is key to stress defense pathways and demonstrate a function for Set4 in regulating repressive, heterochromatin-like environments.

A SUBTILISIN-LIKE SERINE PROTEASE1 (OsSUBSrP1), plays an important role in the wax and cutin pathway, is essential for panicle development in rice

Panicle degeneration is a severe physiological defect and causes reduction in grain yield. In this study, we characterized and presented the functional analysis of our previously reported mutant apa1331 (apical panicle abortion1331) that showed apical spikelet degeneration. The anthers from the apical spikelets of apa1331 were degenerated, pollen-less and showed lack of cuticle formation. Transverse sections showed normal meiosis till stage 5-6, however, defects in post-meiotic microspore development were found at stage 8-9 in apa1331. Measurement of wax and cutin analysis showed a significant reduction in anthers of apa1331 compared to Wildtype (WT). Quantification of H2O2 and MDA has indicated the excessive ROS (reactive oxygen species) in apa1331. Trypan blue staining, and TUNEL assay revealed cell death and excessive DNA fragmentation in apa1331. Map-based cloning and Mutmap analysis identified a candidate gene (LOC_Os04g40720) that is a SUBTILISIN-LIKE SERINE PROTEASE (OsSUBSrP1) which harbored an SNP (A>G) in apa1331. CRISPR-mediated knock-out lines of OsSUBSrP1 displayed spikelet degeneration comparable to apa1331. Global gene expression analysis revealed a significant downregulation of wax and cutin biosynthesis genes e.g., OsWDA1, OsMS2 and OsCER4 in apa1331. Our study reports the novel role of SUBSrP1 in ROS-mediated cell death in panicle development.

The vitamin D receptor is differentially expressed in brain metastatic breast cancer.

Brain metastases affect up to 34% of breast cancer patients treated with trastuzumab (1). Limited treatment options are available for clinical control of brain metastatic breast cancer (2-4). We mined published microarray data (5, 6) to identify genes associated with metastasis to the brain in human breast cancer. This unbiased, global gene expression analysis identified differential expression of the vitamin D (1α,25(OH)2D3) receptor, encoded by VDR, as a transcriptional feature of brain metastasis in patients with breast cancer. Primary tumor expression of VDR was significantly correlated with overall survival in patients with breast cancer. VDR may be of relevance to processes underlying metastasis to the brain in human metastatic breast cancer.

Aldolase B is differentially expressed in brain metastatic breast cancer.

Brain metastases affect up to 34% of breast cancer patients treated with trastuzumab (1). Limited treatment options are available for clinical control of brain metastatic breast cancer (2-4). We mined published microarray data (5, 6) to identify genes associated with metastasis to the brain in human breast cancer. This unbiased, global gene expression analysis identified differential expression of aldolase B, encoded by the gene Aldob, an enzyme functioning in the metabolism of fructose (7, 8), as a transcriptional feature of brain metastasis in patients with breast cancer. Aldolase B may be of relevance to processes underlying metastasis to the brain in human metastatic breast cancer.

Fli1 is differentially expressed in brain metastatic breast cancer.

Brain metastases affect up to 34% of breast cancer patients treated with trastuzumab (1). Limited treatment options are available for clinical control of brain metastatic breast cancer (2-4). We mined published microarray data (5, 6) to identify genes associated with metastasis to the brain in human breast cancer. This unbiased, global gene expression analysis identified Fli1 as a transcriptional feature of brain metastasis in patients with breast cancer. Fli1 may be of relevance to any one of numerous processes involved in metastasis of breast cancers to the brain, including the generation of tumor clones with sufficient oncogenic potential to colonize the brain.