Cells

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14 pages, 2584 KiB

Open AccessArticle

RUNX1 Is Regulated by Androgen Receptor to Promote Cancer Stem Markers and Chemotherapy Resistance in Triple Negative Breast Cancer

by Natalia B. Fernández, Sofía M. Sosa, Justin T. Roberts, María S. Recouvreux, Luciana Rocha-Viegas, Jessica L. Christenson, Nicole S. Spoelstra, Facundo L. Couto, Ana R. Raimondi, Jennifer K. Richer and Natalia Rubinstein

Cells 2023, 12(3), 444; https://doi.org/10.3390/cells12030444 - 29 Jan 2023

Cited by 8 | Viewed by 2899

Abstract

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. The androgen receptor (AR) is expressed in up to [...] Read more.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype for which no effective targeted therapies are available. Growing evidence suggests that chemotherapy-resistant cancer cells with stem-like properties (CSC) may repopulate the tumor. The androgen receptor (AR) is expressed in up to 50% of TNBCs, and AR inhibition decreases CSC and tumor initiation. Runt-related transcription factor 1 (RUNX1) correlates with poor prognosis in TNBC and is regulated by the AR in prostate cancer. Our group has shown that RUNX1 promotes TNBC cell migration and regulates tumor gene expression. We hypothesized that RUNX1 is regulated by the AR and that both may work together in TNBC CSC to promote disease recurrence following chemotherapy. Chromatin immunoprecipitation sequencing (ChIP-seq) experiments in MDA-MB-453 revealed AR binding to RUNX1 regulatory regions. RUNX1 expression is upregulated by dihydrotestosterone (DHT) in MDA-MB-453 and in an AR⁺-TNBC HCI-009 patient-derived xenograft (PDX) tumors (p < 0.05). RUNX1 is increased in a CSC-like experimental model in MDA-MB-453 and SUM-159PT cells (p < 0.05). Inhibition of RUNX1 transcriptional activity reduced the expression of CSC markers. Interestingly, RUNX1 inhibition reduced cell viability and enhanced paclitaxel and enzalutamide sensitivity. Targeting RUNX1 may be an attractive strategy to potentiate the anti-tumor effects of AR inhibition, specifically in the slow-growing CSC-like populations that resist chemotherapy which lead to metastatic disease. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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Review

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19 pages, 2780 KiB

Open AccessReview

The RUNX Family of Proteins, DNA Repair, and Cancer

by Vaidehi Krishnan

Cells 2023, 12(8), 1106; https://doi.org/10.3390/cells12081106 - 07 Apr 2023

Cited by 5 | Viewed by 3505

Abstract

The RUNX family of transcription factors, including RUNX1, RUNX2, and RUNX3, are key regulators of development and can function as either tumor suppressors or oncogenes in cancer. Emerging evidence suggests that the dysregulation of RUNX genes can promote genomic instability in both leukemia [...] Read more.

The RUNX family of transcription factors, including RUNX1, RUNX2, and RUNX3, are key regulators of development and can function as either tumor suppressors or oncogenes in cancer. Emerging evidence suggests that the dysregulation of RUNX genes can promote genomic instability in both leukemia and solid cancers by impairing DNA repair mechanisms. RUNX proteins control the cellular response to DNA damage by regulating the p53, Fanconi anemia, and oxidative stress repair pathways through transcriptional or non-transcriptional mechanisms. This review highlights the importance of RUNX-dependent DNA repair regulation in human cancers. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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14 pages, 779 KiB

Open AccessReview

RUNX3 Meets the Ubiquitin-Proteasome System in Cancer

by Albano Toska, Nikita Modi and Lin-Feng Chen

Cells 2023, 12(5), 717; https://doi.org/10.3390/cells12050717 - 24 Feb 2023

Cited by 3 | Viewed by 2015

Abstract

RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be oncogenic in certain cancers. Many factors account for the tumor suppressor function of RUNX3, which is reflected by its [...] Read more.

RUNX3 is a transcription factor with regulatory roles in cell proliferation and development. While largely characterized as a tumor suppressor, RUNX3 can also be oncogenic in certain cancers. Many factors account for the tumor suppressor function of RUNX3, which is reflected by its ability to suppress cancer cell proliferation after expression-restoration, and its inactivation in cancer cells. Ubiquitination and proteasomal degradation represent a major mechanism for the inactivation of RUNX3 and the suppression of cancer cell proliferation. On the one hand, RUNX3 has been shown to facilitate the ubiquitination and proteasomal degradation of oncogenic proteins. On the other hand, RUNX3 can be inactivated through the ubiquitin–proteasome system. This review encapsulates two facets of RUNX3 in cancer: how RUNX3 suppresses cell proliferation by facilitating the ubiquitination and proteasomal degradation of oncogenic proteins, and how RUNX3 is degraded itself through interacting RNA-, protein-, and pathogen-mediated ubiquitination and proteasomal degradation. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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15 pages, 1244 KiB

Open AccessReview

Role of RUNX3 in Restriction Point Regulation

by Jung-Won Lee, You-Soub Lee, Min-Kyu Kim, Xin-Zi Chi, Dohun Kim and Suk-Chul Bae

Cells 2023, 12(5), 708; https://doi.org/10.3390/cells12050708 - 23 Feb 2023

Cited by 2 | Viewed by 1507

Abstract

A cell cycle is a series of events that takes place in a cell as it grows and divides. At the G₁ phase of cell cycle, cells monitor their cumulative exposure to specific signals and make the critical decision to pass through [...] Read more.

A cell cycle is a series of events that takes place in a cell as it grows and divides. At the G₁ phase of cell cycle, cells monitor their cumulative exposure to specific signals and make the critical decision to pass through the restriction (R)-point. The R-point decision-making machinery is fundamental to normal differentiation, apoptosis, and G₁–S transition. Deregulation of this machinery is markedly associated with tumorigenesis. Therefore, identification of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in tumor biology. RUNX3 is one of the genes frequently inactivated in tumors by epigenetic alterations. In particular, RUNX3 is downregulated in most K-RAS-activated human and mouse lung adenocarcinomas (ADCs). Targeted inactivation of Runx3 in the mouse lung induces adenomas (ADs), and markedly shortens the latency of ADC formation induced by oncogenic K-Ras. RUNX3 participates in the transient formation of R-point-associated activator (RPA-RX3-AC) complexes, which measure the duration of RAS signals and thereby protect cells against oncogenic RAS. This review focuses on the molecular mechanism by which the R-point participates in oncogenic surveillance. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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20 pages, 2413 KiB

Open AccessReview

The RUNX/CBFβ Complex in Breast Cancer: A Conundrum of Context

by Adiba S. Khan, Kirsteen J. Campbell, Ewan R. Cameron and Karen Blyth

Cells 2023, 12(4), 641; https://doi.org/10.3390/cells12040641 - 16 Feb 2023

Cited by 1 | Viewed by 2461

Abstract

Dissecting and identifying the major actors and pathways in the genesis, progression and aggressive advancement of breast cancer is challenging, in part because neoplasms arising in this tissue represent distinct diseases and in part because the tumors themselves evolve. This review attempts to [...] Read more.

Dissecting and identifying the major actors and pathways in the genesis, progression and aggressive advancement of breast cancer is challenging, in part because neoplasms arising in this tissue represent distinct diseases and in part because the tumors themselves evolve. This review attempts to illustrate the complexity of this mutational landscape as it pertains to the RUNX genes and their transcription co-factor CBFβ. Large-scale genomic studies that characterize genetic alterations across a disease subtype are a useful starting point and as such have identified recurring alterations in CBFB and in the RUNX genes (particularly RUNX1). Intriguingly, the functional output of these mutations is often context dependent with regards to the estrogen receptor (ER) status of the breast cancer. Therefore, such studies need to be integrated with an in-depth understanding of both the normal and corrupted function in mammary cells to begin to tease out how loss or gain of function can alter the cell phenotype and contribute to disease progression. We review how alterations to RUNX/CBFβ function contextually ascribe to breast cancer subtypes and discuss how the in vitro analyses and mouse model systems have contributed to our current understanding of these proteins in the pathogenesis of this complex set of diseases. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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17 pages, 1038 KiB

Open AccessReview

The RUNX Family Defines Trk Phenotype and Aggressiveness of Human Neuroblastoma through Regulation of p53 and MYCN

by Kiyohiro Ando and Akira Nakagawara

Cells 2023, 12(4), 544; https://doi.org/10.3390/cells12040544 - 08 Feb 2023

Viewed by 1615

Abstract

The Runt-related transcription factor (RUNX) family, which is essential for the differentiation of cells of neural crest origin, also plays a potential role in neuroblastoma tumorigenesis. Consecutive studies in various tumor types have demonstrated that the RUNX family can play either pro-tumorigenic or [...] Read more.

The Runt-related transcription factor (RUNX) family, which is essential for the differentiation of cells of neural crest origin, also plays a potential role in neuroblastoma tumorigenesis. Consecutive studies in various tumor types have demonstrated that the RUNX family can play either pro-tumorigenic or anti-tumorigenic roles in a context-dependent manner, including in response to chemotherapeutic agents. However, in primary neuroblastomas, RUNX3 acts as a tumor-suppressor, whereas RUNX1 bifunctionally regulates cell proliferation according to the characterized genetic and epigenetic backgrounds, including MYCN oncogenesis. In this review, we first highlight the current knowledge regarding the mechanism through which the RUNX family regulates the neurotrophin receptors known as the tropomyosin-related kinase (Trk) family, which are significantly associated with neuroblastoma aggressiveness. We then focus on the possible involvement of the RUNX family in functional alterations of the p53 family members that execute either tumor-suppressive or dominant-negative functions in neuroblastoma tumorigenesis. By examining the tripartite relationship between the RUNX, Trk, and p53 families, in addition to the oncogene MYCN, we endeavor to elucidate the possible contribution of the RUNX family to neuroblastoma tumorigenesis for a better understanding of potential future molecular-based therapies. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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13 pages, 2331 KiB

Open AccessReview

RUNX3 in Stem Cell and Cancer Biology

by Linda Shyue Huey Chuang, Junichi Matsuo, Daisuke Douchi, Nur Astiana Bte Mawan and Yoshiaki Ito

Cells 2023, 12(3), 408; https://doi.org/10.3390/cells12030408 - 25 Jan 2023

Cited by 6 | Viewed by 2362

Abstract

The runt-related transcription factors (RUNX) play prominent roles in cell cycle progression, differentiation, apoptosis, immunity and epithelial–mesenchymal transition. There are three members in the mammalian RUNX family, each with distinct tissue expression profiles. RUNX genes play unique and redundant roles during development and [...] Read more.

The runt-related transcription factors (RUNX) play prominent roles in cell cycle progression, differentiation, apoptosis, immunity and epithelial–mesenchymal transition. There are three members in the mammalian RUNX family, each with distinct tissue expression profiles. RUNX genes play unique and redundant roles during development and adult tissue homeostasis. The ability of RUNX proteins to influence signaling pathways, such as Wnt, TGFβ and Hippo-YAP, suggests that they integrate signals from the environment to dictate cell fate decisions. All RUNX genes hold master regulator roles, albeit in different tissues, and all have been implicated in cancer. Paradoxically, RUNX genes exert tumor suppressive and oncogenic functions, depending on tumor type and stage. Unlike RUNX1 and 2, the role of RUNX3 in stem cells is poorly understood. A recent study using cancer-derived RUNX3 mutation R122C revealed a gatekeeper role for RUNX3 in gastric epithelial stem cell homeostasis. The corpora of RUNX3^R122C/R122C mice showed a dramatic increase in proliferating stem cells as well as inhibition of differentiation. Tellingly, RUNX3^R122C/R122C mice also exhibited a precancerous phenotype. This review focuses on the impact of RUNX3 dysregulation on (1) stem cell fate and (2) the molecular mechanisms underpinning early carcinogenesis. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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14 pages, 806 KiB

Open AccessReview

The RUNX Family, a Novel Multifaceted Guardian of the Genome

by Bibek Dutta and Motomi Osato

Cells 2023, 12(2), 255; https://doi.org/10.3390/cells12020255 - 07 Jan 2023

Cited by 1 | Viewed by 2107

Abstract

The DNA repair machinery exists to protect cells from daily genetic insults by orchestrating multiple intrinsic and extrinsic factors. One such factor recently identified is the Runt-related transcription factor (RUNX) family, a group of proteins that act as a master transcriptional regulator for [...] Read more.

The DNA repair machinery exists to protect cells from daily genetic insults by orchestrating multiple intrinsic and extrinsic factors. One such factor recently identified is the Runt-related transcription factor (RUNX) family, a group of proteins that act as a master transcriptional regulator for multiple biological functions such as embryonic development, stem cell behaviors, and oncogenesis. A significant number of studies in the past decades have delineated the involvement of RUNX proteins in DNA repair. Alterations in RUNX genes cause organ failure and predisposition to cancers, as seen in patients carrying mutations in the other well-established DNA repair genes. Herein, we review the currently existing findings and provide new insights into transcriptional and non-transcriptional multifaceted regulation of DNA repair by RUNX family proteins. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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14 pages, 1125 KiB

Open AccessReview

RUNX Proteins as Epigenetic Modulators in Cancer

by Hongyang Yi, Yuhao He, Qionghua Zhu and Liang Fang

Cells 2022, 11(22), 3687; https://doi.org/10.3390/cells11223687 - 20 Nov 2022

Cited by 4 | Viewed by 2214

Abstract

RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis [...] Read more.

RUNX proteins are highly conserved in metazoans and perform critical functions during development. Dysregulation of RUNX proteins through various molecular mechanisms facilitates the development and progression of various cancers, where different RUNX proteins show tumor type-specific functions and regulate different aspects of tumorigenesis by cross-talking with different signaling pathways such as Wnt, TGF-β, and Hippo. Molecularly, they could serve as transcription factors (TFs) to activate their direct target genes or interact with many other TFs to modulate chromatin architecture globally. Here, we review the current knowledge on the functions and regulations of RUNX proteins in different cancer types and highlight their potential role as epigenetic modulators in cancer. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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15 pages, 1034 KiB

Open AccessReview

The Roles of RUNX Proteins in Lymphocyte Function and Anti-Tumor Immunity

by Wooseok Seo, Aneela Nomura and Ichiro Taniuchi

Cells 2022, 11(19), 3116; https://doi.org/10.3390/cells11193116 - 03 Oct 2022

Cited by 2 | Viewed by 1775

Abstract

The Runt-related transcription factor (RUNX) family of proteins are crucial for many developmental and immuno-physiological processes. Their importance in cellular and tissue development has been repeatedly demonstrated as they are often found mutated and implicated in tumorigenesis. Most importantly, RUNX have now emerged [...] Read more.

The Runt-related transcription factor (RUNX) family of proteins are crucial for many developmental and immuno-physiological processes. Their importance in cellular and tissue development has been repeatedly demonstrated as they are often found mutated and implicated in tumorigenesis. Most importantly, RUNX have now emerged as critical regulators of lymphocyte function against pathogenic infections and tumorigenic cells, the latter has now revolutionized our current understandings as to how RUNX proteins contribute to control tumor pathogenicity. These multifunctional roles of RUNX in mammalian immune responses and tissue homeostasis have led us to appreciate their value in controlling anti-tumor immune responses. Here, we summarize and discuss the role of RUNX in regulating the development and function of lymphocytes responding to foreign and tumorigenic threats and highlight their key roles in anti-tumor immunity. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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14 pages, 694 KiB

Open AccessReview

RUNX Family in Hypoxic Microenvironment and Angiogenesis in Cancers

by You Mie Lee

Cells 2022, 11(19), 3098; https://doi.org/10.3390/cells11193098 - 01 Oct 2022

Cited by 4 | Viewed by 1915

Abstract

The tumor microenvironment (TME) is broadly implicated in tumorigenesis, as tumor cells interact with surrounding cells to influence the development and progression of the tumor. Blood vessels are a major component of the TME and are attributed to the creation of a hypoxic [...] Read more.

The tumor microenvironment (TME) is broadly implicated in tumorigenesis, as tumor cells interact with surrounding cells to influence the development and progression of the tumor. Blood vessels are a major component of the TME and are attributed to the creation of a hypoxic microenvironment, which is a common feature of advanced cancers and inflamed premalignant tissues. Runt-related transcription factor (RUNX) proteins, a transcription factor family of developmental master regulators, are involved in vital cellular processes such as differentiation, proliferation, cell lineage specification, and apoptosis. Furthermore, the RUNX family is involved in the regulation of various oncogenic processes and signaling pathways as well as tumor suppressive functions, suggesting that the RUNX family plays a strategic role in tumorigenesis. In this review, we have discussed the relevant findings that describe the crosstalk of the RUNX family with the hypoxic TME and tumor angiogenesis or with their signaling molecules in cancer development and progression. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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Other

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10 pages, 1879 KiB

Open AccessOpinion

p53 Deficiency-Dependent Oncogenicity of Runx3

by Kosei Ito, Shohei Otani and Yuki Date

Cells 2023, 12(8), 1122; https://doi.org/10.3390/cells12081122 - 10 Apr 2023

Viewed by 1745

Abstract

The RUNX transcription factors are frequently dysregulated in human cancers, suggesting their potential as attractive targets for drug treatment. However, all three transcription factors have been described as both tumor suppressors and oncogenes, indicating the need to determine their molecular mechanisms of action. [...] Read more.

The RUNX transcription factors are frequently dysregulated in human cancers, suggesting their potential as attractive targets for drug treatment. However, all three transcription factors have been described as both tumor suppressors and oncogenes, indicating the need to determine their molecular mechanisms of action. Although RUNX3 has long been considered a tumor suppressor in human cancers, several recent studies have shown that RUNX3 is upregulated during the development or progression of various malignant tumors, suggesting it may act as a “conditional” oncogene. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. This review describes the evidence for the activities of RUNX3 in human cancer and proposes an explanation for the duality of RUNX3 involving the status of p53. In this model, p53 deficiency causes RUNX3 to become oncogenic, leading to aberrant upregulation of MYC. Full article

(This article belongs to the Special Issue Roles of RUNX Family in Cancer)

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