Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

The elimination of Mcl-1, an anti-apoptotic Bcl-2 family member, is an early and required step for DNA damage-induced apoptosis. The degradation of Mcl-1 can be blocked by proteasome inhibitors, suggesting a role for the ubiquitin proteasome pathway in apoptosis. Here, we demonstrate that Mcl-1 is ubiquinated at five lysines. Biochemical fractionation of cell extracts allowed us to identify a 482 kDa HECT-domain-containing ubiquitin ligase named Mule (Mcl-1 ubiquitin ligase E3) that is both required and sufficient for the polyubiquitination of Mcl-1. Mule also contains a region similar to the Bcl-2 homology region 3 (BH3) domain that allows Mule to specifically interact with Mcl-1. Elimination of Mule expression by RNA interference stabilizes Mcl-1 protein, resulting in an attenuation of the apoptosis induced by DNA-damage agents. Thus, Mule is a unique BH3-containing E3 ubiquitin ligase apical to Bcl-2 family proteins during DNA damage-induced apoptosis.

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Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumor suppressor protein and consequent accumulation of the HIF2α transcription factor 1. Here we show that a small molecule (PT2399) that directly inhibits HIF2α causes tumor regression in preclinical models of primary and metastatic pVHL-defective ccRCC in an on-target fashion. pVHL-defective ccRCC cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers.

Most clear cell renal carcinomas (ccRCCs) are initiated by somatic inactivation of theVHLtumor suppressor gene. TheVHLgene product, pVHL, is the substrate recognition unit of an ubiquitin ligase that targets the HIF transcription factor for proteasomal degradation; inappropriate expression of HIF target genes drives renal carcinogenesis. Loss of pVHL is not sufficient, however, to cause ccRCC. Additional cooperating genetic events, including intragenic mutations and copy number alterations, are required. Common examples of the former are loss-of-function mutations of thePBRM1andBAP1tumor suppressor genes, which occur in a mutually exclusive manner in ccRCC and define biologically distinct subsets of ccRCC.PBRM1encodes the Polybromo- and BRG1-associated factors-containing complex (PBAF) chromatin remodeling complex component BRG1-associated factor 180 (BAF180). Here we identified ccRCC lines whose ability to proliferate in vitro and in vivo is sensitive to wild-type BAF180, but not a tumor-associated BAF180 mutant. Biochemical and functional studies linked growth suppression by BAF180 to its ability to form a canonical PBAF complex containing BRG1 that dampens the HIF transcriptional signature.

Single- or few-layered h-BN nanosheets (BNNSs) are analogous to graphene and possess unique properties. However, their technological applications were severely hindered by the low production efficiency of BNNSs. We reported here a study in which BNNSs were efficiently produced by exfoliating bulk h-BN powder in thionyl chloride without using any dispersion agents. The BNNSs yield was as high as 20%, and it could be doubled through the second round of exfoliation of the h-BN precipitate. Microscopic results revealed that the BNNSs generally consisted of 3-20 layers. Pd nanoparticles were successfully immobilized and uniformly distributed on BNNS surfaces through the deposition-precipitation method. The resultant Pd-BNNS catalyst exhibited high catalytic activity and recyclability for the hydrogenation of nitro aromatics, demonstrating that BNNSs served as a promising platform to fabricate heterogeneous catalysts.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function mutations in the tumor suppressor gene RB1. The canonical function of the RB1 gene product, pRB, is to repress the E2F transcription factor family, but pRB also functions to regulate cellular differentiation in part through its binding to the histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype in part by sustaining expression of the neuroendocrine transcription factor ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A +/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and suggests that KDM5 inhibitors should be explored as treatments for SCLC.

Boron nitride nanosheets (BNNS) were used to anchor bimetallic Pd-Fe nanoparticles for Suzuki-Miyaura coupling catalysts. The bimetallic nanoparticles were found to be core-shell in structure, and their formation was likely facilitated by their interactions with the BNNS. The Pd-Fe/BNNS catalysts were highly effective in representative Suzuki-Miyaura reactions, with performances matching or exceeding those of the state-of-the-art methods. Specifically, the superior catalytic activities were characterized by generally shortened reaction times, minimal Pd usage, excellent reusability of the catalysts and high or nearly quantitative conversion yields in a benign solvent system without the need for any special conditions, such as ligands and surfactants or inert gas protection. The obvious advantages of the Pd-Fe/BNNS over similar catalysts based on other supports, such as reduced graphene oxide (rGO), suggest that BNNS may be developed into a versatile platform for many other important catalytic reactions.