Condensin II protein dysfunction impacts mitochondrial respiration and stress response

Deutschman, Emily; Ward, Jacqueline R.; Kumar, Avinash; Ray, Greeshma; Welch, Nicole; Lemieux, Madeleine E.; Dasarathy, S.; Longworth, Michelle S.

doi:10.1242/jcs.233783

Cited by 8 publications

(5 citation statements)

References 103 publications

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“…It has been suggested in the literature that subunits of condensing I and condensin II are associated with tumorigenesis [ 34 ]. Recently, studies have reported that NCAPD3 localizes to the exterior surface of mitochondria and affects mitochondrial oxidative stress responses [ 35 ]. The research on NCAPD3 mainly focuses on its role in condensation and segregation during cell division, little is known about its bio-functions and molecular mechanisms in tumors.…”

Section: Discussionmentioning

confidence: 99%

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer

Jing

Liu

et al. 2022

J Exp Clin Cancer Res

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Background NCAPD3 is one of the three non-SMC subunits of condensin II complex, which plays an important role in the chromosome condensation and segregation during mitosis. Notably, elevated levels of NCAPD3 are found in many somatic cancers. However, the clinical role, biological functions of NCAPD3 in cancers especially in colorectal cancer (CRC) and the underlying molecular mechanisms remain poorly elucidated. Methods Clinical CRC and adjacent normal tissues were used to confirm the expression of NCAPD3. The association of NCAPD3 expression with clinicopathological characteristics and patient outcomes were analyzed by using online database. In vivo subcutaneous tumor xenograft model, NCAPD3 gene knockout following azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced tumor mouse model, Co-IP, western blot, qRT-PCR, IHC, ChIP assays and cell functional assays were used to investigate the biological functions of NCAPD3 in CRC and the underlying molecular mechanisms. Results NCAPD3 was overexpressed in CRC tissues and positively correlated with poor prognosis of CRC patients. NCAPD3 knockout suppressed CRC development in AOM/DSS induced and xenograft mice models. Moreover, we found that NCAPD3 promoted aerobic glycolysis in CRC. Mechanistically, NCAPD3 up-regulated the level of c-Myc and interacted with c-Myc to recruit more c-Myc to the gene promoter of its downstream glycolytic regulators GLUT1, HK2, ENO1, PKM2 and LDHA, and finally enhanced cellular aerobic glycolysis. Also, NCAPD3 increased the level of E2F1 and interacted with E2F1 to recruit more E2F1 to the promoter regions of PDK1 and PDK3 genes, which resulted in the inhibition of PDH activity and TCA cycle. Conclusions Our data demonstrated that NCAPD3 promoted glucose metabolism reprogramming and enhanced Warburg effect in colorectal tumorigenesis and CRC progression. These findings reveal a novel mechanism underlying NCAPD3 mediated CRC cell growth and provide new targets for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer

Jing

Liu

et al. 2022

J Exp Clin Cancer Res

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“…In prostate cancer, NCAPD3 has also been shown to activate E2F1 and STAT3 and drive prostate cancer progression ( 73 ). In addition, NCAPD3 is present in the outer mitochondrial membrane and regulates oxidative stress in the mitochondria, which is not dependent on glycolysis and does not affect the number of mitochondria ( 74 ). Ultimately, in vitro experiments also confirmed that the knockdown of NCAPD3 resulted in a significant decrease in cell viability and colony number in BC cell lines MDA-MB-231 and BCAP-37 and a significant slowdown in scratch healing in MDA-MB-231 cells.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial DNA methylation is a predictor of immunotherapy response and prognosis in breast cancer: scRNA-seq and bulk-seq data insights

Chen

et al. 2023

Front. Immunol.

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BackgroundAlterations in Mitochondrial DNA methylation (MTDM) exist in many tumors, but their role in breast cancer (BC) development remains unclear.MethodsWe analyzed BC patient data by combining scRNA-seq and bulk sequencing. Weighted co-expression network analysis (WGCNA) of TCGA data identified mitochondrial DNA methylation (MTDM)-associated genes in BC. COX regression and LASSO regression were used to build prognostic models. The biological function of MTDM was assessed using various methods, such as signaling pathway enrichment analysis, copynumber karyotyping analysis, and quantitative analysis of the cell proliferation rate. We also evaluated MTDM-mediated alterations in the immune microenvironment using immune microenvironment, microsatellite instability, mutation, unsupervised clustering, malignant cell subtype differentiation, immune cell subtype differentiation, and cell-communication signature analyses. Finally, we performed cellular experiments to validate the role of the MTDM-associated prognostic gene NCAPD3 in BC.ResultsIn this study, MTDM-associated prognostic models divided BC patients into high/low MTDM groups in TCGA/GEO datasets. The difference in survival time between the two groups was statistically significant (P<0.001). We found that high MTDM status was positively correlated with tumor cell proliferation. We analyzed the immune microenvironment and found that low-MTDM group had higher immune checkpoint gene expression/immune cell infiltration, which could lead to potential benefits from immunotherapy. In contrast, the high MTDM group had higher proliferation rates and levels of CD8+T cell exhaustion, which may be related to the secretion of GDF15 by malignant breast epithelial cells with a high MTDM status. Cellular experiments validated the role of the MTDM-associated prognostic gene NCAPD3 (the gene most positively correlated with epithelial malignant cell proliferation in the model) in BC. Knockdown of NCAPD3 significantly reduced the activity and proliferation of MDA-MB-231 and BCAP-37 cells, and significantly reduced their migration ability of BCAP-37 cell line.ConclusionThis study presented a holistic evaluation of the multifaceted roles of MTDM in BC. The analysis of MTDM levels not only enables the prediction of response to immunotherapy but also serves as an accurate prognostic indicator for patients with BC. These insightful discoveries provide novel perspectives on tumor immunity and have the potentially to revolutionize the diagnosis and treatment of BC.

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“…Studies in thoroughbred horses have identified a candidate gene JAM3, involved in spermatogenesis in horses and genes CALR and DNMT1 mediating fertility and pregnancy in mares [48,49]. The dysfunction of Condensin II protein in humans affects mitochondrial respiration and mitochondrial oxidative stress response [50]. Other researchers have found that the PRDX2 gene plays a functional role in oxidative stress in equine species; JUNB, PIN1, and KANK2 genes are involved in repair processes in ligament and tendon injuries; and LDLR regulates lipid metabolism, which affects the risks of degenerative suspensory ligament desmitis disease [51].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Diversity of Stallions of Different Breeds in Russia

Дементьева

Nikitkina

Shcherbakov

et al. 2023

Genes

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The specifics of breeding and selection significantly affect genetic diversity and variability within a breed. We present the data obtained from the genetic analysis of 21 thoroughbred and warmblood horse breeds. The most detailed information is described from the following breeds: Arabian, Trakehner, French Trotter, Standardbred, and Soviet Heavy Horse. The analysis of 509,617 SNP variants in 87 stallions from 21 populations made it possible to estimate the genetic diversity at the genome-wide level and distinguish the studied horse breeds from each other. In this study, we searched for heterozygous and homozygous ROH regions, evaluated inbreeding using FROH analysis, and generated a population structure using Admixture 1.3 software. Our findings indicate that the Arabian breed is an ancestor of many horse breeds. The study of the full-genome architectonics of breeds is of great practical importance for preserving the genetic characteristics of breeds and managing breeding. Studies were carried out to determine homozygous regions in individual breeds and search for candidate genes in these regions. Fifty-six candidate genes for the influence of selection pressure were identified. Our research reveals genetic diversity consistent with breeding directions and the breeds’ history of origin.

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Condensin II protein dysfunction impacts mitochondrial respiration and stress response

Cited by 8 publications

References 103 publications

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer

NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer

Mitochondrial DNA methylation is a predictor of immunotherapy response and prognosis in breast cancer: scRNA-seq and bulk-seq data insights

The Genetic Diversity of Stallions of Different Breeds in Russia

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