As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein–protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)–MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.

Class switch DNA recombination (CSR) is the mechanism that diversifies the biological effector functions of antibodies. Activation-induced cytidine deaminase (AID), a key CSR player, targets IgH switch (S) regions, which contain 5′-AGCT-3′ repeats in their core. How AID is recruited to S regions remains unclear. Here we show that 14-3-3 adaptor proteins play an important role in CSR. 14-3-3 proteins specifically bind 5′-AGCT-3′ repeats, are upregulated in B cells undergoing CSR and are recruited together with AID to the S regions involved in CSR events (Sμ→Sγ1, Sμ→Sγ3 or Sμ→Sα). Moreover, blocking 14-3-3 by difopein, deficiency in 14-3-3γ or expression of a dominant negative 14-3-3σ mutant impaired recruitment of AID to S regions and decreased CSR. Finally, 14-3-3 proteins interact directly with AID and enhance AID-mediated in vitro DNA deamination, further emphasizing the important role of these adaptors in CSR.

The family of 14-3-3 proteins has emerged as critical regulators of diverse cellular responses under both physiological and pathological conditions. Here, we report an important role of 14-3-3 in tumorigenesis through a mechanism that involves anoikis resistance. 14-3-3 is up-regulated in a number of cancer types, including lung cancer. Through an RNAi approach using human lung adenocarcinomaderived A549 cells as a model system, we have found that knockdown of a single isoform of 14-3-3 is sufficient to restore the sensitivity of cancer cells to anoikis and impair their anchorage-independent growth. Enhanced anoikis appears to be mediated in part by upregulated BH3-only proteins, Bad and Bim, coupled with decreased Mcl-1, resulting in the subsequent activation of Bax. This study suggests a model in which anchorage-independent growth of lung cancer cells requires the presence of 14-3-3. This work not only reveals a critical role of 14-3-3 in anoikis suppression in lung cancer cells, but also identifies and validates 14-3-3 as a potential molecular target for anticancer therapeutic development. molecular target ͉ RNAi ͉ tumorigenesis ͉ apoptosis ͉ BH3-only

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10−08). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D–LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis.