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Abstract Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to meet the high energy and biosynthetic demands required for their proliferation. High mobility group A1 (HMGA1) is a structural transcription factor and frequently overexpressed in human colorectal cancer (CRC). Here, we show that HMGA1 promotes CRC progression by driving lipid synthesis in a AOM/DSS-induced CRC mouse model. Using conditional knockout (Hmga1 △IEC) and knock-in (Hmga1 IEC-OE/+) mouse models, we demonstrate that HMGA1 enhances CRC cell proliferation and accelerates tumor development by upregulating fatty acid synthase (FASN). Mechanistically, HMGA1 increases the transcriptional activity of sterol regulatory element-binding protein 1 (SREBP1) on the FASN promoter, leading to increased lipid accumulation in intestinal epithelial cells. Moreover, a high-fat diet exacerbates CRC progression in Hmga1 △IEC mice, while pharmacological inhibition of FASN by orlistat reduces tumor growth in Hmga1 IEC-OE/+ mice. Our findings suggest that targeting lipid metabolism could offer a promising therapeutic strategy for CRC.

Abstract Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.

Abstract Aberrant stem cell-like activity and impaired differentiation are central to the development of colorectal cancer (CRC). To identify functional mediators of these key cellular programs, we engineer a dual endogenous reporter system by genome-editing the SOX9 and KRT20 loci of human CRC cell lines to express fluorescent reporters, broadcasting aberrant stem cell-like and differentiation activity, respectively. By applying a CRISPR screen targeting 78 epigenetic regulators with 542 sgRNAs to this platform, we identify factors that contribute to stem cell-like activity and differentiation in CRC. Perturbation single cell RNA sequencing (Perturb-seq) of validated hits nominate SMARCB1 of the BAF complex (also known as SWI/SNF) as a negative regulator of differentiation across an array of neoplastic colon models. SMARCB1 is a dependency and required for in vivo growth of human CRC models. These studies highlight the utility of biologically designed endogenous reporter platforms to uncover regulators with therapeutic potential.

Abstract The formal C–C bond insertion into aldehydes is an attractive methodology for the assembly of homologated carbonyl compounds. However, the homologation of aldehydes has been limited to diazo approach and the enantioselective reaction was rarely developed. Herein, we report an asymmetric formal C–C bond insertion into aldehydes through diyne cyclization strategy. In the presence of Cu(I)/SaBOX catalyst, this method leads to the efficient construction of versatile axially chiral naphthylpyrroles in moderate to excellent yields with good to excellent enantioselectivities. This protocol represents a rare example of asymmetric formal C–C bond insertion into aldehydes using non-diazo approach. The combined experimental and computational mechanistic studies reveal the reaction mechanism, origin of regioselectivity and stereoselectivity. Notably, the chiral phosphine ligand derived from synthesized axially chiral skeleton was proven to be applicable to asymmetric catalysis.

Abstract Combination chemotherapy is crucial for successfully treating cancer. However, the enormous number of possible drug combinations means discovering safe and effective combinations remains a significant challenge. To improve this process, we conduct large-scale targeted CRISPR knockout screens in drug-treated cells, creating a genetic map of druggable genes that sensitize cells to commonly used chemotherapeutics. We prioritize neuroblastoma, the most common extracranial pediatric solid tumor, where ~50% of high-risk patients do not survive. Our screen examines all druggable gene knockouts in 18 cell lines (10 neuroblastoma, 8 others) treated with 8 widely used drugs, resulting in 94,320 unique combination-cell line perturbations, which is comparable to the largest existing drug combination screens. Using dense drug-drug rescreening, we find that the top CRISPR-nominated drug combinations are more synergistic than standard-of-care combinations, suggesting existing combinations could be improved. As proof of principle, we discover that inhibition of PRKDC, a component of the non-homologous end-joining pathway, sensitizes high-risk neuroblastoma cells to the standard-of-care drug doxorubicin in vitro and in vivo using patient-derived xenograft (PDX) models. Our findings provide a valuable resource and demonstrate the feasibility of using targeted CRISPR knockout to discover combinations with common chemotherapeutics, a methodology with application across all cancers.

Abstract Hydrogen peroxide (H2O2) electrosynthesis through oxygen reduction reaction (ORR) is drawing worldwide attention, whereas suffering seriously from the sluggish oxygen evolution reaction (OER) and the difficult extraction of thermodynamically unstable H2O2. Herein, we present an electrosynthesis protocol involving coupling ORR-to-H2O2 with waste polyethylene terephthalate (PET) upcycling and the first H2O2 conversion strategy. Ni-Mn bimetal- and onion carbon-based catalysts are designed to catalyze ORR-to-H2O2 and ethylene glycol electrooxidation with the Faradaic efficiency of 97.5% (H2O2) and 93.0% (formate). This electrolysis system runs successfully at only 0.927 V to achieve an industrial-scale current density of 400 mA cm−2, surpassing all reported H2O2 electrosynthesis systems. H2O2 product is upgraded through two downstream routes of converting H2O2 into sodium perborate and dibenzoyl peroxide. Techno-economic evolution highlights the high gross profit of the ORR || PET upcycling protocol over HER || PET upcycling and ORR || OER. This work provides an energy-saving methodology for the electrosynthesis of H2O2 and other chemicals.

Reliable, multiplexed gene editing to uncover synergies between targets remains challenging. Here, the authors engineer AsCas12a and the crRNA to improve double knockout for synthetic sick/lethal interaction genetic screening.

Effective combination therapies to improve the efficacy of BET inhibitors are currently under investigation. Here, the authors examine palbociclib and paclitaxel as two promising candidates for combination therapies with BET inhibition in breast cancer and investigate the dynamics of resistance to these combinations through DNA barcoding and mathematical modelling.

Axially chiral compounds have widespread use in asymmetric catalysis. Here, the authors disclose a highly enantioselective synthesis of axially chiral o-naphthoquinones by chiral phosphoric acid catalysis and central-to-axial chirality conversion.

Core regulatory transcription factors are usually regulated by cell-type specific super enhancers (SEs). Here, the authors screen for chemical probes able to distinguish between SE-driven and promoter-driven transcription and find that histone deacetylases are selectively required for core regulatory transcription.

BET-bromodomain inhibitors could be used to treat medulloblastoma tumors with Myc amplifications. Here, the authors show that both the response and resistance to BET inhibitors in mice is mediated by bHLH/homeobox transcription factors.

Immune cells may become less responsive, or ‘exhausted’, upon chronic viral infection, but the underlying mechanism and crosstalk are still unclear. Here the authors show that, upon chronic hepatitis C virus (HCV) infection, natural killer cell exhaustion is induced by NKG2A signalling to instruct downstream exhaustion of CD8+ T cells and HCV persistence.

Axially chiral arylpyrroles are structural motifs often found in natural and medicinal products. Here, the authors report the atroposelective synthesis of axially chiral arylpyrrole derivatives, which proved to be efficient chiral ligands for asymmetric catalysis, through desymmetrization and kinetic resolution.

The original PDF version of this Article contained an error in Table 3, in which all chemical structures were omitted and only the numerical data was shown. This has been corrected in the PDF version of the Article. The HTML version was correct from the time of publication.