TGFβ Promotes Genomic Instability after Loss of RUNX3

Krishnan, Vaidehi; Chong, Yu; Tan, Tuan Zea; Kulkarni, Madhura; Rahmat, Muhammad Bakhait Bin; Tay, Lavina Sierra; Sankar, Haresh; Jokhun, Doorgesh Sharma; Ganesan, Amudha; Chuang, Linda Shyue Huey; Voon, Dominic Chih-Cheng; Shivashankar, G. V.; Thiery, Jean Paul; Ito, Yoshiaki

doi:10.1158/0008-5472.can-17-1178

Cited by 22 publications

(23 citation statements)

References 51 publications

(55 reference statements)

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“…Also, it remains an open question whether cytoplasmic RUNX3 holds some oncogenic effects, since to date no publication refers to the possible pro‐tumour role of cytoplasmic RUNX3, independent of the loss of its tumour‐suppressor effects due to nuclear dislocation. And this may well explain the two‐edge role of RUNX3 in different tumours, because it seems like that RUNX3 functions as an oncogenic factors in some rare cases 29‐32 . RUNX3 cytoplasmic retention was already reported by other group to be associated with poor prognosis in colorectal cancer 33 .…”

Section: Discussionmentioning

confidence: 78%

Inhibition of PIM1 attenuates the stem cell–like traits of breast cancer cells by promoting RUNX3 nuclear retention

Liu

Chen

et al. 2020

J Cellular Molecular Medi

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Finding out the driver gene critical for the maintenance of breast cancer stem cells (BrCSCs) is important for designing a new strategy to eradicate these cells to improve patient's prognosis. Here, in our study, we revealed that PIM1, an oncogenic serine‐threonine kinase and a well‐proven contributor to the tumorigenesis of breast cancer, was involved in BrCSCs regulation and promised to be a new target for eradicating BrCSCs. In brief, PIM1 could enhance the stem cell–like traits of breast cancer cells by promoting the phosphorylation and cytoplasmic localization of RUNX3. The nuclear dislocation of RUNX3 disabled this tumour suppressor and led to breast cancer cells gaining stem cell–like traits. Inhibition of PIM1 significantly induced the nuclear retention of RUNX3, recovered its transcriptional function and attenuated the stem cell–like properties of breast cancer cells. Those findings deepened our understanding of PIM1's oncogenic effect, underlining the significance of PIM1 in designing a new strategy aimed at BrCSCs.

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Section: Discussionmentioning

confidence: 78%

Inhibition of PIM1 attenuates the stem cell–like traits of breast cancer cells by promoting RUNX3 nuclear retention

Liu

Chen

et al. 2020

J Cellular Molecular Medi

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“…The down-regulation of the redox modulator, heme oxygenase-1 (HO-1), due to a low concentration of RUNX3, increased oxidative DNA damage and ultimately destroyed genome integrity and triggered cellular senescence accompanied by tumor-promoting inflammatory cytokine expression and acquisition of senescence-related secretory behavior. Tumor-bearing TGF-β gene expression signatures and RUNX3 loss showed higher levels of genomic instabilities ( 55 ), suggesting a novel connection between microenvironment-derived extrinsic TGF-β signaling and intrinsic RUNX3 inactivation in genomic instability. In addition, TGF-β induced EMT is highly noticed in Runx3 null gastric epithelial lines, emphasizing the role of RUNX3 in repression of TGF-β induced EMT ( 56 ).…”

Section: Runx3 Mediated Regulation Of Inflammatory Cells In Tumor Micmentioning

confidence: 99%

Emerging role of RUNX3 in the regulation of tumor microenvironment

Manandhar

Lee

2018

BMB Rep.

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A number of genes have been therapeutically targeted to relieve cancer, but cancer relapse is still a growing issue. The concept that the surrounding tumor environment is critical for the progression of cancer may foster an answer to the issue of cancer malignancy. Runt domain transcription factors (RUNX1, 2, and 3) are evolutionarily conserved and have been intensively studied for their roles in normal development and pathological conditions. During tumor growth, a hypoxic microenvironment and infiltration of the tumor by immune cells are common phenomena. In this review, we briefly introduce the consequences of hypoxia and immune cell infiltration into the tumor microenvironment with a focus on RUNX3 as a critical regulator. Furthermore, based on our current knowledge of the functional role of RUNX3 in hypoxia and immune cell maintenance, a probable therapeutic intervention is suggested for the effective management of tumor growth and malignancy.

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“…We noticed that the predicted upstream regulators were very similar for each type of senescence. More specifically, Cluster-1 showed upstream regulators TP53, a marker for DNA-damage [13, 25–27]. We also saw Interferon term IFNA2, suggesting a more proinflammatory profile [28].…”

Section: Resultsmentioning

confidence: 99%

Single Cell Transcriptomics Reveals Global Markers of Transcriptional Diversity Across Different Forms of Cellular Senescence

Klark

et al. 2021

Preprint

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Cellular Senescence is a state of irreversible cell cycle arrest, and the accumulation of senescent cells contributes to agerelated organismal decline. The detrimental effects of cellular senescence are due to the senescence associated secretory phenotype (SASP), an array of signaling molecules and growth factors secreted by senescent cells that contribute to the terile inflammation associated with aging tissues. Recent studies, both in vivo and in vitro, have highlighted the heterogeneous nature of the senescence phenotype. In particular, single cell transcriptomics has revealed that Oncogene Induced Senescence (OIS) is characterized by the presence of subpopulations of cells expressing different SASP profiles. We have generated a comprehensive dataset via single-cell transcriptional profiling of genetically homogenous clonal cell lines from different forms of senescence, including OIS, Replicative Senescence (RS), and DNA Damage Induced Senescence (DDIS). We identified subpopulations of cells that are common to all three major forms of senescence and show that the expression profiles of these subpopulations are driven by markers formerly identified in individual forms of senescence. These common signatures are characterized by chromatin modifiers, inflammation, extracellular matrix remodeling, and Ribosomal protein expression. The expression patterns of these subpopulations recapitulate primary and secondary senescence, a phenomenon where a preexisting (primary) senescent cell induces senescence in a neighboring (secondary) cell through cell-to-cell contact. Since it is still unclear what type of senescence occurs in-vivo with age, it is important to know that the formation of primary and secondary populations is common to multiple types of senescence since this mechanism could help explain how senescent cells accumulate in aged organisms. Finally, we show that these subpopulations show differential susceptibility to the senolytic agent Navitoclax, suggesting that senolytic agents targeting the apoptotic pathways may be clearing only a subset of senescent cells based on their inflammatory profiles in-vivo.

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TGFβ Promotes Genomic Instability after Loss of RUNX3

Cited by 22 publications

References 51 publications

Inhibition of PIM1 attenuates the stem cell–like traits of breast cancer cells by promoting RUNX3 nuclear retention

Inhibition of PIM1 attenuates the stem cell–like traits of breast cancer cells by promoting RUNX3 nuclear retention

Emerging role of RUNX3 in the regulation of tumor microenvironment

Single Cell Transcriptomics Reveals Global Markers of Transcriptional Diversity Across Different Forms of Cellular Senescence

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