Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples

Morden, Claire R.; Farrell, Ally C.; Sliwowski, Mirka; Lichtensztejn, Zelda; Altman, Alon D.; Nachtigal, Mark W.; McManus, Kirk J.

doi:10.1016/j.ygyno.2021.02.038

Cited by 28 publications

(25 citation statements)

References 52 publications

(78 reference statements)

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“…Using a combination of siRNA and CRISPR/Cas9 approaches, they demonstrated that reduced expression corresponded with significant changes in nuclear areas, micronucleus formation and chromosome numbers. They further showed that CIN was prevalent and dynamic over an ∼3-month timeframe, which is key given recent evidence showing that CIN is both pervasive and dynamic in ascites (an accumulation of abdominal fluid containing tumor cells) and solid tumor samples isolated from patients with high-grade serous ovarian cancer ( Penner-Goeke et al, 2017 ; Morden et al, 2021 ). Collectively, these data identify SKP1 as a novel CIN gene and further suggest that reduced expression may contribute to cancer pathogenesis.…”

Section: Aberrant Skp1 Expression Induces Cin That...mentioning

confidence: 93%

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Thompson

Rutherford

Lepage

et al. 2022

Front. Cell Dev. Biol.

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The S-phase Kinase-Associated Protein 1 (SKP1) is a core component of the SKP1, Cullin 1, F-box protein (SCF) complex, an E3 ubiquitin ligase that serves to poly-ubiquitinate a vast array of protein targets as a signal for their proteasomal degradation, thereby playing a critical role in the regulation of downstream biological processes. Many of the proteins regulated by SKP1 and the SCF complex normally function within pathways that are essential for maintaining genome stability, including DNA damage repair, apoptotic signaling, and centrosome dynamics. Accordingly, aberrant SKP1 and SCF complex expression and function is expected to disrupt these essential pathways, which may have pathological implications in diseases like cancer. In this review, we summarize the central role SKP1 plays in regulating essential cellular processes; we describe functional models in which SKP1 expression is altered and the corresponding impacts on genome stability; and we discuss the prevalence of SKP1 somatic copy number alterations, mutations, and altered protein expression across different cancer types, to identify a potential link between SKP1 and SCF complex dysfunction to chromosome/genome instability and cancer pathogenesis. Ultimately, understanding the role of SKP1 in driving chromosome instability will expand upon our rudimentary understanding of the key events required for genome/chromosome stability that may aid in our understanding of cancer pathogenesis, which will be critical for future studies to establish whether SKP1 may be useful as prognostic indicator or as a therapeutic target.

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Section: Aberrant Skp1 Expression Induces Cin That...mentioning

confidence: 93%

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Thompson

Rutherford

Lepage

et al. 2022

Front. Cell Dev. Biol.

Self Cite

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“…, oncogenes, tumor suppressor, DNA repair genes) contributing to intratumoral heterogeneity. We demonstrated that CIN is dynamic in HGSOC patient samples throughout their course of treatment, and that CIN levels are typically higher in chemoresistant compared to chemosensitive patients [30] . The ability of L-Rham to kill patient-derived HGSOC cells was unaffected by CIN status or chemotherapy-sensitivity, suggesting GAELs may be effective agents to improve outcome in HGSOC patients.…”

Section: Discussionmentioning

confidence: 79%

“…HGSOC is a genetically unstable disease [ [24] , [25] , [26] , [27] ] characterized by a type of genomic instability called chromosome instability (CIN) [ [28] , [29] , [30] , [31] , [32] ]. CIN is defined by an increase in the rate at which whole chromosomes or large parts are gained or lost [33] , and is associated with intratumoral heterogeneity, poor patient outcome, and chemoresistance [ [33] , [34] , [35] , [36] , [37] , [38] ].…”

Section: Discussionmentioning

confidence: 99%

Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

Nachtigal

Musaphir

Dhiman

et al. 2021

Translational Oncology

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Highlights L-Rham induces apoptosis-independent cell death in high grade serous ovarian cancer (HGSOC) cells. L-Rham-induced cell death is dose and time dependent in HGSOC cells grown as 2D or 3D cultures. L-Rham is as effective as paclitaxel to reduce tumor burden and metastasis in a CAM model. L-Rham significantly reduces tumor formation in a low tumor burden model. L-Rham blocks ascites formation.

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“…Accordingly, functional studies are now required to determine the specific outcomes driven by aberrant expression and/or function of each SCF complex member gene and its impact on substrate accumulation to better understand the molecular determinants giving rise to cancer development, which will be critical to develop innovative precision medicine strategies to better combat the disease. For instance, as aberrant SCF complex function is associated with CIN [ 9 , 10 , 12 ], developing biomarkers to detect abnormal SCF complex expression could aid early diagnosis in cancers that exhibit high levels of CIN, including colorectal [ 99 ] and ovarian cancers [ 100 , 101 ], where early disease detection will be critical to ultimately improve patient outcomes [ 102 , 103 ]. Thus, future studies need to be designed that compile and analyze patient sample datasets for mutations, CNAs and methylation changes with matched normal samples and patient outcomes to gain a comprehensive understanding of how genetic alterations are associated with disease and their impact on patient outcomes.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

Gudiño

Farrell

Neudorf

et al. 2021

IJMS

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The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.

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Chromosome instability is prevalent and dynamic in high-grade serous ovarian cancer patient samples

Cited by 28 publications

References 52 publications

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Aberrant SKP1 Expression: Diverse Mechanisms Impacting Genome and Chromosome Stability

Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

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