The RUNX Family of Proteins, DNA Repair, and Cancer

Krishnan, Vaidehi

doi:10.3390/cells12081106

Cited by 12 publications

(3 citation statements)

References 99 publications

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“…The RUNX family has been identified as a novel multifaceted guardian of the genome ( Dutta et al, 2023 ). Dysregulation of RUNX1 genes can promote genomic instability in solid cancers by impairing DNA repair mechanisms ( Krishnan, 2023 ). ARID1B is a key component of BAF complex of the SWI/SNF chromatin-remodeling family, which regulates gene expression during cellular development and influences the DNA damage response ( Watanabe et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Evolutionary history of adenomas to colorectal cancer in FAP families

Yang,

Xiang,

Chen

et al. 2024

Front. Genet.

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ObjectiveFamilial adenomatous polyposis (FAP) is a genetic syndrome characterized by multiple polyps at various evolutionary stages, which, if left untreated, inevitably progress to colorectal cancer (CRC). In this study, we present a comprehensive analysis of the evolutionary history of FAP-CRC from precancerous adenoma to carcinoma.DesignTissues were collected from gastrointestinal endoscopy or surgical resection. Exome sequencing was performed on multiple regions of adenocarcinoma (n = 8), villous adenoma (n = 10), tubular adenoma (n = 9) and blood samples were obtained from 9 patients belonging to 7 Chinese FAP families. Phylogenetic trees were reconstructed, and evolutionary analysis was conducted to reveal the temporal sequence of events leading to CRC.ResultsInherited germline mutation sites in APC gene were identified in FAP01 (p.S1281*, COSM19212), FAP03 (p.S384Tfs*19), FAP04 (p.E1538*, COSM6041693), FAP05 (p.Q1062*, COSM3696862), and FAP07-FAP09 (p.V677Sfs*3). Notably, p.V677Sfs*3 mutation was recognized as a novel germline mutation in APC, supported by evidence of genotype-phenotype correlation in pedigree analysis. Adenomas exhibited lower mutational rates than FAP-CRC and displayed recurrent alterations in well-known chromosomal instability (CIN) genes (APC, RAS, SMAD4 and TP53) and DNA damage repair genes (SUZ12, KMT2C, BCLAF1, RUNX1, and ARID1B), suggesting the presence of genomic instability. Furthermore, a progressive increase in the HRD score (a measure of “genomic scars”) was observed from tubular adenomas to villous adenomas and ultimately to carcinomas. TP53 emerged as the primary driver gene for adenoma-carcinoma transition, with driver mutations consistently appearing simultaneously rather than sequentially acquired from adenomas to carcinomas. Clonal evolution demonstrated that liver metastases can originate from the same cancer-primed cell present in a primary cancerous lesion.ConclusionWe identified a novel pathogenic variant in APC, namely, p.V677Sfs*3. The process of carcinogenesis in FAP-CRC supports the classical cancerization model, where an initial APC mutation leads to the activation of the WNT signaling pathway and CIN. Subsequently, additional mutations occur in other putative CIN genes (e.g., DNA repair, chromatin remodeling), ultimately leading to the development of microsatellite stable (MSS) tumors. Our study provides a comprehensive understanding of the genomic landscapes that underlie the transition from adenoma to carcinoma.

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Section: Discussionmentioning

confidence: 99%

Evolutionary history of adenomas to colorectal cancer in FAP families

Yang,

Xiang,

Chen

et al. 2024

Front. Genet.

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“…Considering the role of RUNX-p53 interaction in carcinogenesis in general, Bae et al proposed a two-step tumour-suppressive model in which RUNX proteins prevent adenoma formation at first, whilst p53 functions at later stages to prevent adenocarcinoma [ 166 ]. In the regulation of the DNA damage response, both RUNX1 and RUNX3 form a complex with p53 and promote the transactivation of p53 target genes ( BAX , PUMA , NOXA , and p21 ), whilst the interaction of RUNX2 with p53 suppresses the transactivation of p53 target genes such as p21 , WAF1 , and BAX [ 167 ], so the potential SL interaction between p53 and RUNX genes in HCC requires further investigation. A recent comprehensive bioinformatics study tested 14 tumour-suppressor and 3194 druggable genes (including RUNX1 , RUNX2 , and RUNX3 ) using functional similarity and differential gene expression analysis for SL interaction identification in HCC, and a total of 272 potential SL pairs were revealed, whilst RUNX genes did not pass initial screening tests [ 165 ].…”

Section: Discussionmentioning

confidence: 99%

Multiple Roles of the RUNX Gene Family in Hepatocellular Carcinoma and Their Potential Clinical Implications

Krajnović,

Kožik,

Božović

et al. 2023

Cells

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Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by a high resistance to conventional chemotherapy, late diagnosis, and a high mortality rate. It is necessary to elucidate the molecular mechanisms involved in hepatocarcinogenesis to improve diagnosis and treatment outcomes. The Runt-related (RUNX) family of transcription factors (RUNX1, RUNX2, and RUNX3) participates in cardinal biological processes and plays paramount roles in the pathogenesis of numerous human malignancies. Their role is often controversial as they can act as oncogenes or tumour suppressors and depends on cellular context. Evidence shows that deregulated RUNX genes may be involved in hepatocarcinogenesis from the earliest to the latest stages. In this review, we summarise the topical evidence on the roles of RUNX gene family members in HCC. We discuss their possible application as non-invasive molecular markers for early diagnosis, prognosis, and development of novel treatment strategies in HCC patients.

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“…Runt-related transcription factor-1 (RUNX1) is a member of the core-binding factor family of transcription factors involved in transcriptional regulation of gene expression (Krishnan 2023 ; Rozen et al 2023 ). RUNX gene family is composed of three members (RUNX1, RUNX2 and RUNX3), which encode the DNA-binding (α) subunits of a family of transcription factors that orchestrate proliferation, differentiation, and cell survival in multiple lineages.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

Chen,

Wang,

Zhang

et al. 2024

Funct Integr Genomics

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Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI.

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The RUNX Family of Proteins, DNA Repair, and Cancer

Cited by 12 publications

References 99 publications

Evolutionary history of adenomas to colorectal cancer in FAP families

Evolutionary history of adenomas to colorectal cancer in FAP families

Multiple Roles of the RUNX Gene Family in Hepatocellular Carcinoma and Their Potential Clinical Implications

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

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