Sgo1 is a potential therapeutic target for hepatocellular carcinoma

Wang, Lyu Han; Yen, Chia Jui; Li, Tian Neng; Elowe, Sabine; Wang, Wen-Ching; Wang, Lily

doi:10.18632/oncotarget.2764

Cited by 30 publications

(30 citation statements)

References 35 publications

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“…Reduction of Sgo1 by siRNA in cultured cells [51,52,55] by haploinsufficiency (-/+) in transgenic models [56][57][58] or expression of an aberrant form (e.g. loss, dominant negative) of Sgo1 in human lung, liver, and colon cancer [59][60][61][62][63] leads to cohesinopathy in mitotic chromosomes (premature chromosome separation) and in the centrosome (mitosis with multipolar spindles). The Sgo1 defectmediated cohesinopathy subsequently provokes the mitotic spindle checkpoint.…”

Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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Section: Shugoshin 1 Haploinsufficient Mice (Sgo1-/+) Showed Cohesinomentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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“…Sgo1 −/+ model has shown unique transcriptomic signatures at the tissue/organ level and cancer proneness in certain organs including colon, lung, and liver (Rao et al., 2016; Yamada et al., 2012, 2015, 2016). In humans, the homolog SgoL1 is frequently mutated or abnormally expressed in cancers, affecting the mitotic process (Iwaizumi et al., 2009; Kahyo et al., 2011; Matsuura et al., 2013; Wang et al., 2015). Congenital mutations in human SgoL1 lead to chronic atrial and intestinal dysrhythmia syndrome, affecting the heart and gut rhythm (Chetaille et al., 2014).…”

Section: Introductionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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“…Reduced SGOL1 expression leads to premature loss of sister chromatid missegregation, centromeric cohesion, and mitotic arrest [28,29]. SGOL1 is a potential therapeutic target for HCC because of its role in cell division [30]. Here we show that SGOL1 was the most highly enriched gene detected using the CRISPR screen, indicating that knockout of SGOL1 contributed to sorafenib resistance.…”

Section: Discussionmentioning

confidence: 66%

Genome-wide CRISPR screen reveals SGOL1 as a druggable target of sorafenib-treated hepatocellular carcinoma

Sun

Yang

et al. 2018

Laboratory Investigation

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The genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen is a powerful tool used to identify therapeutic targets that can be harnessed for cancer treatment. This study aimed to assess the efficacy of genome-wide CRISPR screening to identify druggable genes associated with sorafenib-treated hepatocellular carcinoma (HCC). A genome-scale CRISPR knockout (GeCKO v2) library containing 123,411 single guide RNAs (sgRNAs) was used to identify loss-of-function mutations conferring sorafenib resistance upon HCC cells. Resistance gene screens identified SGOL1 as an indicator of prognosis of patients treated with sorafenib. Of the 19,050 genes tested, the knockout screen identified inhibition of SGOL1 expression as the most-effective genetic suppressor of sorafenib activity. Analysis of the survival of 210 patients with HCC after hepatic resection revealed that high SGOL1 expression shortened overall survival (P = 0.021). Further, matched pairs analysis of the TCGA database revealed that SGOL1 is differentially expressed. When we used a lentivirus Cas9 vector to determine the effect of targeting SGOL1 with a specific sgRNA in HCC cells, we found that SGOL1 expression was efficiently inhibited and that loss of SGOL1 was associated with sorafenib resistance. Further, loss of SGOL1 from HCC cell decreased the cytotoxicity of sorafenib in vivo. We conclude that the CRISPR screen is a powerful tool for therapeutic target analysis of sorafenib treatment and that SGOL1 serves as a druggable target for HCC treated with sorafenib and an indicator of prognosis.

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Sgo1 is a potential therapeutic target for hepatocellular carcinoma

Cited by 30 publications

References 35 publications

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Genome-wide CRISPR screen reveals SGOL1 as a druggable target of sorafenib-treated hepatocellular carcinoma

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