PBRM1 acts as a p53 lysine-acetylation reader to suppress renal tumor growth.

p53 acetylation is indispensable for its transcriptional activity and tumor suppressive function. However, the identity of reader protein(s) for p53 acetylation remains elusive. PBRM1, the second most highly mutated tumor suppressor gene in kidney cancer, encodes PBRM1. Here, we identify PBRM1 as a reader for p53 acetylation on lysine 382 (K382Ac) through its bromodomain 4 (BD4). Notably, mutations on key residues of BD4 disrupt recognition of p53 K382Ac. The mutation in BD4 also reduces p53 binding to promoters of target genes such as CDKN1A (p21). Consequently, the PBRM1 BD4 mutant fails to fully support p53 transcriptional activity and is defective as a tumor suppressor. We also find that expressions of PBRM1 and p21 correlate with each other in human kidney cancer samples. Our findings uncover a tumor suppressive mechanism of PBRM1 in kidney cancer and provide a mechanistic insight into the crosstalk between p53 and SWI/SNF complexes

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

A Negative Regulatory Loop between MicroRNA and Hox Gene Controls Posterior Identities in Caenorhabditis elegans

MicroRNAs (miRNAs) have been found to regulate gene expression across eukaryotic species, but the function of most miRNA genes remains unknown. Here we describe how the analysis of the expression patterns of a well-conserved miRNA gene, mir-57, at cellular resolution for every minute during early development of Caenorhabditis elegans provided key insights in understanding its function. Remarkably, mir-57 expression shows strong positional bias but little tissue specificity, a pattern reminiscent of Hox gene function. Despite the minor defects produced by a loss of function mutation, overexpression of mir-57 causes dramatic posterior defects, which also mimic the phenotypes of mutant alleles of a posterior Hox gene, nob-1, an Abd homolog. More importantly, nob-1 expression is found in the same two posterior AB sublineages as those expressing mir-57 but with an earlier onset. Intriguingly, nob-1 functions as an activator for mir-57 expression; it is also a direct target of mir-57. In agreement with this, loss of mir-57 function partially rescues the nob-1 allele defects, indicating a negative feedback regulatory loop between the miRNA and Hox gene to provide positional cues. Given the conservation of the miRNA and Hox gene, the regulatory mechanism might be broadly used across species. The strategy used here to explore mir-57 function provides a path to dissect the regulatory relationship between genes

Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis

The brain is a major site of relapse for several cancers, yet deciphering the mechanisms of brain metastasis remains a challenge because of the complexity of the brain tumor microenvironment (TME). To define the molecular landscape of brain metastasis from intact tissue in vivo, we employ an RNA-sequencing-based approach, which leverages the transcriptome of xenografts and distinguishes tumor cell and stromal gene expression with improved sensitivity and accuracy. Our data reveal shifts in epithelial and neuronal-like lineage programs in malignant cells as they adapt to the brain TME and the reciprocal neuroinflammatory response of the stroma. We identify several transcriptional hallmarks of metastasis that are specific to particular regions of the brain, induced across multiple tumor types, and confirmed in syngeneic models and patient biopsies. These data may serve as a resource for exploring mechanisms of TME co-adaptation within, as well as across, different subtypes of brain metastasis.We thank Sally Adua for critical review of the manuscript. This work wasfunded by grants R01CA166376, R01CA191489, and W81XWH-15-1-0117and the Beatrice Kleinberg Neuwirth Fund (to D.X.N.); Yale Lung CancerSPORE grant P50CA196530 (to K.P. and D.X.N.); Yale SPORE in Skin Cancergrants P50 CA121974, K24CA172123, and R01 CA216846 (to H.M.K.);MINECO grants SAF2017-89643-R and SAF2015-62547-ERC, Bristol-MyersSquibb-MRA Young Investigator Award 2017, Fundacio ́n Ramo ́n Areces,and CLIP CRI Award 2018 (to M.V.); La Caixa-Severo Ochoa InternationalPhD Program Fellowship (to L.Z.); and FCT PhD Fellowship SFRH/BD/100089/2014 (to C.M.). M.V. is a Ramo ́n y Cajal Investigator (RYC-2013-13365) and member of EMBO YIP (4053). K.D.P. was supported by grantT32 CA193200, W.L.C. by grant DGE-1122492, and E.W. by grant T32GM100884S

MKL1-actin pathway restricts chromatin accessibility and prevents mature pluripotency activation

MKL1 is a key transcriptional co-activator of actin cytoskeleton genes. Here the authors show that MKL1 activation in somatic cells reduces chromatin accessibility and hinders full reprogramming to pluripotency. Reduction of MKL1, disruption of actin cytoskeleton and its links to the nucleus relieve this repression