Hippo Pathway-related Genes Expression Is Deregulated in Myeloproliferative Neoplasms

Abstract Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased proliferation of precursor and mature myeloid cells. MPN patients may present driver mutations in JAK2, MPL, and CALR genes, which are essential to describe the molecular mechanisms of MPN pathogenesis. Despite all the new knowledge on MPN pathogenesis, many questions remain to be answered to develop effective therapies to cure MPN or impair its progression to acute myeloid leukemia. The present study examined the expression levels of the Hippo signaling pathway members in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as the role that they play in disease pathogenesis. The Hippo pathway is a tumor suppressor pathway that participates in the regulation of cell proliferation, differentiation, and death. Our main findings were: (i) expression of tumor suppressor genes from Hippo pathway were downregulated and seemed to be associated with cell resistance to apoptosis and increased proliferation rate; and (ii) Hippo pathway-related gene expression was associated with mutation status in ET and PMF patients. Therefore, the decreased expression of Hippo pathway-related genes may contribute to the malignant phenotype, apoptosis resistance, and cell proliferation in MPN pathogenesis.

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RASSF1A-Mediated Suppression of Estrogen Receptor Alpha (ERα)-Driven Breast Cancer Cell Growth Depends on the Hippo-Kinases LATS1 and 2

Cells ◽

10.3390/cells10112868 ◽

2021 ◽

Vol 10 (11) ◽

pp. 2868

Author(s):

Sven Roßwag ◽

Jonathan P. Sleeman ◽

Sonja Thaler

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Tumor Suppressor ◽

Estrogen Receptor Alpha ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Hippo Signaling ◽

Breast Cancers ◽

Receptor Alpha ◽

And Function

Around 70% of breast cancers express the estrogen receptor alpha (ERα). This receptor is of central importance for breast cancer development and estrogen-dependent tumor growth. However, the molecular mechanisms that are responsible for the control of ERα expression and function in the context of breast carcinogenesis are complex and not fully understood. In previous work, we have demonstrated that the tumor suppressor RASSF1A suppresses estrogen-dependent growth of breast cancer cells through a complex network that keeps ERα expression and function under control. We observed that RASSF1A mediates the suppression of ERα expression through modulation of the Hippo effector Yes-associated protein 1 (YAP1) activity. Here we report that RASSF1A-mediated alteration of YAP1 depends on the Hippo-kinases LATS1 and LATS2. Based on these results, we conclude that inactivation of RASSF1A causes changes in the function of the Hippo signaling pathway and altered activation of YAP1, and as a consequence, increased expression and function of ERα. Thus, the inactivation of RASSF1A might constitute a fundamental event that supports the initiation of ERα-dependent breast cancer. Furthermore, our results support the notion that the Hippo pathway is important for the suppression of luminal breast cancers, and that the tumor-suppressor function of RASSF1A depends on LATS1 and LATS2.

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Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

10.21203/rs.3.rs-15912/v1 ◽

2020 ◽

Author(s):

Changran Wei ◽

Xiangqi Li

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Breast Cancer Cell Lines ◽

Hippo Signaling ◽

Luminal A ◽

Ki 67 ◽

Her 2

Abstract Background Breast cancer (BC) can be separated into four molecular subclassifications including Lumina1 A, Lumina1 B, HER-2 overexpression and Basal-like subtype. These classifications are based on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2) and cell proliferation antigen (Ki-67). The Hippo signaling pathway plays an indispensable role in BC. The YAP1 gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study set out to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC. Methods Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro in order to study effect of VP on proliferation and apoptosis on these three molecular BC subtypes. Results Our experimental results show that VP inhibits cell proliferation, YAP-TEAD interaction and its downstream target expression. VP also induces tumor cell apoptosis, and promotes the cleavage of Caspase-9 and PARP in various molecular subtypes of BC cells. Conclusion These findings provide a basis for VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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A myeloid tumor suppressor role for NOL3

Journal of Experimental Medicine ◽

10.1084/jem.20162089 ◽

2017 ◽

Vol 214 (3) ◽

pp. 753-771 ◽

Cited By ~ 3

Author(s):

Robert F. Stanley ◽

Richard T. Piszczatowski ◽

Boris Bartholdy ◽

Kelly Mitchell ◽

Wendy M. McKimpson ◽

...

Keyword(s):

Tumor Suppressor ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Underlying Disease ◽

Driver Mutations ◽

Stem Cell Population ◽

Myeloid Malignancies ◽

Cd34 Cells ◽

Oncogenic Driver ◽

Molecular Aberrations

Despite the identification of several oncogenic driver mutations leading to constitutive JAK–STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3−/− MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3−/−-induced JAK–STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and Myc. Nol3−/− MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.

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Verteporfin inhibits cell proliferation and induces apoptosis in different subtypes of breast cancer cell lines without light activation

BMC Cancer ◽

10.1186/s12885-020-07555-0 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Changran Wei ◽

Xiangqi Li

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Breast Cancer Cell Lines ◽

Cancer Tissue ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B

Abstract Background Breast cancer (BC) can be divided into five subtypes: Lumina1A, Lumina1B, HER-2 overexpression, Basal-like and Normal breast-like subtype, based on the differently expressed genes in breast cancer tissue. The Hippo signaling pathway plays an indispensable role in BC. The YAP gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study aimed to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC. Methods Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro to study effects of VP on proliferation and apoptosis of these three molecular BC subtypes. Results Our experimental results showed that VP inhibited cell proliferation, YAP-TEAD interaction and expression of its downstream targets. VP also induced tumor cell apoptosis, and promoted the cleavage of Caspase-9 and PARP in the cells of various molecular subtypes of BC. Conclusion These findings provide a basis for the use of VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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Thrombocytosis in children and adolescents—classification, diagnostic approach, and clinical management

Annals of Hematology ◽

10.1007/s00277-021-04485-0 ◽

2021 ◽

Author(s):

Clemens Stockklausner ◽

◽

C. M. Duffert ◽

H. Cario ◽

R. Knöfler ◽

...

Keyword(s):

Clinical Management ◽

Molecular Mechanisms ◽

Myeloproliferative Neoplasms ◽

Pediatric Population ◽

Primary Myelofibrosis ◽

Driver Mutations ◽

Gene Encoding ◽

Clinical Complications ◽

Genes Encoding ◽

Infection And Inflammation

AbstractSecondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor’s effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.

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Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

10.21203/rs.3.rs-15912/v3 ◽

2020 ◽

Author(s):

changran Wei ◽

xiangqi Li

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Breast Cancer Cell Lines ◽

Cancer Tissue ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B

Abstract Background: Breast cancer (BC) can be divided into five subtypes: Lumina1A, Lumina1B, HER-2 overexpression, Basal-like and Normal breast-like subtype, based on the differently expressed genes in breast cancer tissue. The Hippo signaling pathway plays an indispensable role in BC. The YAP gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study aimed to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC.Methods: Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro to study effects of VP on proliferation and apoptosis of these three molecular BC subtypes. Results: Our experimental results showed that VP inhibited cell proliferation, YAP-TEAD interaction and expression of its downstream targets. VP also induced tumor cell apoptosis, and promoted the cleavage of Caspase-9 and PARP in the cells of various molecular subtypes of BC. Conclusion: These findings provide a basis for the use of VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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Verteporfin Inhibits Cell Proliferation and Induces Apoptosis in Different Subtypes of Breast Cancer Cell Lines Without Light Activation

10.21203/rs.3.rs-15912/v2 ◽

2020 ◽

Author(s):

changran Wei ◽

xiangqi Li

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Breast Cancer Cell Lines ◽

Cancer Tissue ◽

Hippo Signaling ◽

Luminal A ◽

Luminal B

Abstract Background: Breast cancer (BC) can be separated into five subtypes, including Lumina1A, Lumina1B, HER-2 overexpression, Basal-like and Normal breast-like subtype according to the differently expressed genes in breast cancer tissue.. The Hippo signaling pathway plays an indispensable role in BC. The YAP1 gene is a terminal effector of Hippo pathway, and hyperactivation of YAP mediates tumorigenesis. As an inhibitor of YAP, non-photoactivated verteporfin (VP) can inhibit YAP-mediated tumor proliferation and angiogenesis by eliminating its interaction with TEAD. This study set out to determine the effect and molecular mechanisms of VP-mediated inhibition of YAP in different subtypes of BC.Methods: Luminal A, Luminal B and Basal-like BC cells were cultivated in vitro in order to study effect of VP on proliferation and apoptosis on these three molecular BC subtypes. Results: Our experimental results show that VP inhibits cell proliferation, YAP-TEAD interaction and its downstream target expression. VP also induces tumor cell apoptosis, and promotes the cleavage of Caspase-9 and PARP in various molecular subtypes of BC cells. Conclusion: These findings provide a basis for VP as a potential anti-tumor therapeutic for BC by targeting the Hippo pathway effector YAP.

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NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

The Journal of Cell Biology ◽

10.1083/jcb.201009069 ◽

2011 ◽

Vol 193 (4) ◽

pp. 633-642 ◽

Cited By ~ 89

Author(s):

Sandra Habbig ◽

Malte P. Bartram ◽

Roman U. Müller ◽

Ricarda Schwarz ◽

Nikolaos Andriopoulos ◽

...

Keyword(s):

Cell Proliferation ◽

Cellular Proliferation ◽

Nuclear Translocation ◽

Hippo Pathway ◽

Negative Regulator ◽

Hippo Signaling ◽

Transcriptional Coactivator ◽

Hippo Signaling Pathway ◽

The Hippo Pathway ◽

Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

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Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence

Cells ◽

10.3390/cells9010171 ◽

2020 ◽

Vol 9 (1) ◽

pp. 171

Author(s):

Chiharu Miyajima ◽

Yuki Kawarada ◽

Yasumichi Inoue ◽

Chiaki Suzuki ◽

Kana Mitamura ◽

...

Keyword(s):

Cell Proliferation ◽

Tumor Suppressor ◽

Cellular Senescence ◽

Hippo Pathway ◽

Physiological Role ◽

Underlying Mechanism ◽

Binding Motif ◽

Dependent Manner ◽

Transcriptional Coactivator ◽

Tumor Suppressor P53

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.

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A tale of two cell-fates: role of the Hippo signaling pathway and transcription factors in early lineage formation in mouse preimplantation embryos

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa052 ◽

2020 ◽

Vol 26 (9) ◽

pp. 653-664

Author(s):

Challis Karasek ◽

Mohamed Ashry ◽

Chad S Driscoll ◽

Jason G Knott

Keyword(s):

Signaling Pathway ◽

Cell Fate ◽

Molecular Mechanisms ◽

Hippo Pathway ◽

Cell Mass ◽

Preimplantation Embryos ◽

Hippo Signaling ◽

Cell Fate Decisions ◽

Hippo Signaling Pathway ◽

The Hippo Pathway

Abstract In mammals, the first cell-fate decision occurs during preimplantation embryo development when the inner cell mass (ICM) and trophectoderm (TE) lineages are established. The ICM develops into the embryo proper, while the TE lineage forms the placenta. The underlying molecular mechanisms that govern lineage formation involve cell-to-cell interactions, cell polarization, cell signaling and transcriptional regulation. In this review, we will discuss the current understanding regarding the cellular and molecular events that regulate lineage formation in mouse preimplantation embryos with an emphasis on cell polarity and the Hippo signaling pathway. Moreover, we will provide an overview on some of the molecular tools that are used to manipulate the Hippo pathway and study cell-fate decisions in early embryos. Lastly, we will provide exciting future perspectives on transcriptional regulatory mechanisms that modulate the activity of the Hippo pathway in preimplantation embryos to ensure robust lineage segregation.

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