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Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC. Proteomics can aid in the identification of molecular subtypes in cancers. Here, the authors perform proteomic profiling of 124 paired oesophageal cancer and adjacent non-tumour tissues and identify two subtypes that are associated with patient survival for therapeutic targeting.

The translesion DNA synthesis (TLS) pathway mediated by proliferating cell nuclear antigen (PCNA) monoubiquitination is an essential mechanism by which cancer cells bypass DNA damage caused by DNA damage to maintain genomic stability and cell survival. Chromatin assembly factor 1 subunit A (CHAF1A) traditionally promotes histone assembly during DNA replication. Here, we revealed that CHAF1A is a novel regulator of the TLS pathway in cancer cells. CHAF1A promotes restart and elongation of the replication fork under DNA replication stress. Mechanistically, the C-terminal domain of CHAF1A directly interacts with E3 ubiquitin ligase RAD18, enhancing RAD18 binding on the stalled replication fork. CHAF1A facilitates PCNA K164 monoubiquitination mediated by RAD18, thereby promoting the recruitment of Y-family DNA polymerases and enhancing cancer cell resistance to DNA damage. In addition, CHAF1A-mediated RAD18 recruitment and PCNA monoubiquitination are independent of the CHAF1A-PCNA interaction and its histone assembly function. Taken together, these findings improve our understanding of the mechanisms that regulate the TLS pathway and provide insights into the relationship between CHAF1A and DNA replication stress in cancer cells. Highlights CHAF1A promotes UV-mediated PCNA K164 monoubiquitination in cancer cells. CHAF1A is a new regulator of translesion DNA synthesis pathway in cancer cells. CHAF1A accelerates RAD18 recruitment in the stalled replication forks by directly interacting with RAD18.

(1) Background: Esophageal cancer (EC) is an important global health challenge. Due to the lack of necessary biomarkers and therapeutic targets, the survival of EC patients is poor. The EC proteomic data of 124 patients recently published by our group provides a database for research in this field. (2) Methods: Bioinformatics analysis was used to identify DNA replication and repair-related proteins in EC. Proximity ligation assay, colony formation assay, DNA fiber assay, and flow cytometry were used to study the effects of related proteins on EC cells. Kaplan–Meier survival analysis was used to evaluate the relationship between gene expression and the survival time of EC patients. (3) Results: Chromatin assembly factor 1 subunit A (CHAF1A) was highly correlated with proliferating cell nuclear antigen (PCNA) expression in EC. CHAF1A and PCNA colocalized in the nucleus of EC cells. Compared with the knockdown of CHAF1A or PCNA alone, the double knockdown of CHAF1A and PCNA could significantly inhibit EC cell proliferation. Mechanistically, CHAF1A and PCNA synergistically accelerated DNA replication and promoted S-phase progression. EC patients with high expression of both CHAF1A and PCNA had a worse survival rate. (4) Conclusion: we identify CHAF1A and PCNA as key cell cycle-related proteins leading to the malignant progression of EC, and these proteins could serve as important prognostic biomarkers and targets for EC.

Anillin (ANLN) is a mitosis-related protein that promotes contractile ring formation and cytokinesis, but its cell cycle-dependent degradation mechanisms in cancer cells remain unclear. Here, we show that high expression of ANLN promotes cytokinesis and proliferation in esophageal squamous cell carcinoma (ESCC) cells and is associated with poor prognosis in ESCC patients. Furthermore, the findings of the study showed that the deubiquitinating enzyme USP10 interacts with ANLN and positively regulates ANLN protein levels. USP10 removes the K11- and K63-linked ubiquitin chains of ANLN through its deubiquitinase activity and prevents ANLN ubiquitin-mediated degradation. Importantly, USP10 promotes contractile ring assembly at the cytokinetic furrow as well as cytokinesis by stabilizing ANLN. Interestingly, USP10 and the E3 ubiquitin ligase APC/C co-activator Cdh1 formed a functional complex with ANLN in a non-competitive manner to balance ANLN protein levels. In addition, the macrolide compound FW-04-806 (F806), a natural compound with potential for treating ESCC, inhibited the mitosis of ESCC cells by targeting USP10 and promoting ANLN degradation. F806 selectively targeted USP10 and inhibited its catalytic activity but did not affect the binding of Cdh1 to ANLN and alters the balance of the USP10-Cdh1-ANLN complex. Additionally, USP10 expression was positively correlated with ANLN level and poor prognosis of ESCC patients. Overall, targeting the USP10-ANLN axis can effectively inhibit ESCC cell-cycle progression.

Anillin (ANLN) is a cytoskeletal binding protein involved in mitosis. ANLN is located in the nucleus during interphase and in the cytoplasmic contractile rings during mitosis. Our previous studies found that ANLN is abnormally overexpressed in esophageal squamous cell carcinoma (ESCC), promoting cell division by regulating contractile ring localization. However, the exact function of ANLN in the nucleus remains unclear. Here, we found that the expression of ANLN in the nucleus is associated with poor prognosis in ESCC patients, rather than in the cytoplasm. Protein mass spectrometry and bioinformatics analysis revealed that ANLN is related to DNA synthesis, and proliferating cell nuclear antigen (PCNA) is found to be a potential interacting protein of ANLN. PCNA directly interacts with the PIP box domain of ANLN and co-localizes in the nucleus. ANLN promotes DNA replication and S phase progression in a PCNA dependent manner and independent with the cytoskeletal function of ANLN. Importantly, ANLN is involved in transletion synthesis (TLS), a type of DNA synthesis under stress, by promoting PCNA monoubiquitination at K164 residue. Mechanistically, ANLN binds and recruits the E3 ligase RAD18 to promote PCNA monoubiquitination and DNA polymerase eta loading under UV radiation conditions. Consistently, depletion of ANLN leads to increased genomic instability and increased sensitivity to UV radiation. The findings of the study showed that ANLN in the nucleus as a protein scaffold is involved in UV induced DNA synthesis pathway, providing new insights into the function and mechanism of ANLN in cancer cells.

The translesion DNA synthesis (TLS) pathway mediated by proliferating cell nuclear antigen (PCNA) monoubiquitination is an essential mechanism by which cancer cells bypass DNA damage caused by DNA replication stress to maintain genomic stability and cell survival. Chromatin assembly factor 1 subunit A (CHAF1A) traditionally promotes histone assembly during DNA replication. Here, we revealed that CHAF1A is a novel regulator of the TLS pathway. High expression of CHAF1A is significantly associated with poor prognosis in cancer patients. CHAF1A promotes fork restart under DNA replication stress and maintains genome integrity. CHAF1A enhances the interaction between PCNA and E3 ubiquitin protein ligase RAD18 and promotes PCNA monoubiquitination, thereby promoting the recruitment of Y-family DNA polymerase Pol η and enhancing cancer cell resistance to stimuli that trigger replication fork blockade. Mechanistically, CHAF1A-mediated PCNA monoubiquitination is independent of CHAF1A-PCNA interaction. CHAF1A interacts with both RAD18 and replication protein A2 (RPA2), mediating RAD18 binding on chromatin in response to DNA replication stress. Taken together, these findings improve our understanding of the mechanisms that regulate the TLS pathway and provide insights into the relationship between CHAF1A and the malignant progression of cancers.

Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis. Elevated plasma LDL cholesterol levels increase the risk of atherosclerotic cardiovascular disease. Here, the authors show that inhibition of MT1-MMP reduces plasma LDL cholesterol levels and the risk of atherosclerosis, indicating the potential of MT1-MMP inhibition as a lipid-lowering therapy.

Introduction: Interstitial nephritis related to novel oral anticoagulants was only reported in sporadic case reports and none was accompanied by anticoagulants related nephropathy (ARN). Case Report: We presented here a case of biopsy-proven subacute interstitial nephritis (SubAIN) accompanied by ARN after oral dabigatran to alarm clinicians. This case manifested with gross hematuria, acute kidney injury, slightly prolonged thrombin time, moderate anemia, moderate proteinuria, a large quantity of intratubular hemoglobin casts confirmed by hemoglobin antibody immunohistochemical staining which presumed to occur around 1 week after dabigatran and subacute interstitial nephritis accompanied by focal proliferative glomerulonephritis. Serum creatinine level did not continue to elevate after discontinuation of the oral anticoagulant. With the subsequent supportive therapy, it decreased to some extent then reduced to normal with the help of prednisone (half of the full dose). Conclusions: When we came across a patient who manifested as hematuria or acute kidney injury with a history of anticoagulants usage, we should think of ARN and pay more attention on history collection. Secondly, subacute interstitial nephritis may coexist with ARN. Thirdly, hemoglobin immunohistochemical staining may be helpful to make it clear whether the intra-tubular protein casts came from red blood cells. In addition, for those patients who may have decreased kidney function, anticoagulants dose should be reduced to prevent the occurrence of ARN.

ANKRD17 has recently been implicated in intellectual disability (ID) and autism spectrum disorder (ASD); however, the underlying molecular mechanisms remain unclear. Using trio whole-exome sequencing (Trio-WES) and chromosomal microarray analysis (CMA), we identified two unrelated cases with novel de novo heterozygous ANKRD17 variants. Case 1 describes a fetus with multiple congenital anomalies, where genetic analysis revealed a microdeletion at 4q13.3 truncating the ANKRD17 gene. Case 2 involves a 12-year-old male presenting with mild ID and progressive social impairments, associated with a NM_032217.5: c.1252 C > T (p.Arg418*) variation in ANKRD17 . Our study highlighted in mouse models an association between Ankrd17 haploinsufficiency and deficits in social behavior, spatial learning and memory, as well as elevated anxiety. Furthermore, our studies suggest dysregulation of synaptic proteins and mitochondrial function, along with impaired neural circuits following Ankrd17 knockdown. These results expand the genetic and phenotypic spectrum of ANKRD17 -related disorders, underscore the critical role of mitochondrial dysfunction in the pathophysiology of ANKRD17 -related ID and ASD.

There is growing evidence that cooking oil fumes (COFs) are harmful indoor air pollutants. However, there is a dearth of research investigating whether maternal COFs exposure during pregnancy may affect children’s autistic-like behaviors in China. This study aimed to explore this association, and examine the effects of different cooking fuels and ventilation methods used by mothers on the presence of autistic-like behaviors. This study analyzed the survey data of the Longhua Child Cohort Study in 2017 with a total of 62,372 mothers enrolled in this study. A self-administrative questionnaire was used to collect information on socio-demographic characteristics, cooking habits during pregnancy, and autistic-like behaviors (measured using the Autism Behavior Checklist). After adjusting for potential confounders, the results showed that compared with children whose mothers never cooked during pregnancy, children whose mothers cooked sometimes, often, always during pregnancy had the higher risk of autistic-like behaviors. As the amounts of COFs exposed to and the frequency of cooking during pregnancy increased, the risk of a child’s autistic-like behaviors also increased. Mothers using natural gas as cooking fuels had a lower risk of their child having autistic-like behaviors, compared with mothers using coal or other cooking fuels. Furthermore, pregnant women using ventilation measures during cooking significantly decreased likelihood of the presence of autistic-like behaviors in their children. These results suggest that maternal exposure to COFs during pregnancy may increase the likelihood of the presence of autistic-like behaviors in offspring. These findings support a recommendation that pregnant women should avoid exposure to COFs and use clean fuels and ventilation equipment in kitchens to reduce the risk of autistic-like behaviors in children.