Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway
In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Aleksandra Toloczko, Fusheng Guo, Hiu-Fung Yuen, Qing Wen, Stephen A. Wood, Yan Shan Ong, Pei Yi Chan, Asfa Alli Shaik, Jayantha Gunaratne, Mark J. Dunne, Wanjin Hong, Siew Wee Chan Tags: Tumor and Stem Cell Biology Source Type: research
MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumo...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Paulina Marona, Judyta Gorka, Zofia Mazurek, Waclaw Wilk, Janusz Rys, Marcin Maȷka, Jolanta Jura, Katarzyna Miekus Tags: Tumor and Stem Cell Biology Source Type: research
Exercise-Induced Catecholamines Activate the Hippo Tumor Suppressor Pathway to Reduce Risks of Breast Cancer Development
Strong epidemiologic evidence documents the protective effect of physical activity on breast cancer risk, recurrence, and mortality, but the underlying mechanisms remain to be identified. Using human exercise–conditioned serum for breast cancer cell incubation studies and murine exercise interventions, we aimed to identify exercise factors and signaling pathways involved in the exercise-dependent suppression of breast cancer. Exercise-conditioned serum from both women with breast cancer (n = 20) and healthy women (n = 7) decreased MCF-7 (hormone-sensitive) and MDA-MB-231 (hormone-insensitive) breast cancer cell viability...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Christine Dethlefsen, Louise S. Hansen, Christian Lillelund, Christina Andersen, Julie Gehl, Jesper F. Christensen, Bente K. Pedersen, Pernille Hojman Tags: Tumor and Stem Cell Biology Source Type: research
FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2-Mediated Phosphorylation of CENP-A
The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorag...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Mamoru Takada, Weiguo Zhang, Aussie Suzuki, Taruho S. Kuroda, Zhouliang Yu, Hiroyuki Inuzuka, Daming Gao, Lixin Wan, Ming Zhuang, Lianxin Hu, Bo Zhai, Christopher J. Fry, Kerry Bloom, Guohong Li, Gary H. Karpen, Wenyi Wei, Qing Zhang Tags: Molecular and Cellular Pathobiology Source Type: research
Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1
The Hippo pathway regulates cell proliferation, apoptosis, and stem cell self-renewal, and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers, but the underlying mechanisms are not fully understood. Here, we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Yuan Si, Xinyan Ji, Xiaolei Cao, Xiaoming Dai, Lingyi Xu, Hongxia Zhao, Xiaocan Guo, Huan Yan, Haitao Zhang, Chu Zhu, Qi Zhou, Mei Tang, Zongping Xia, Li Li, Yu-Sheng Cong, Sheng Ye, Tingbo Liang, Xin-Hua Feng, Bin Zhao Tags: Molecular and Cellular Pathobiology Source Type: research
Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis
Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24−) still retain aggressive phenotypes in vitro and in vivo. Here, we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24− cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histologic types of cancer. Nuclear...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Jason E. Duex, Charles Owens, Ana Chauca-Diaz, Garrett M. Dancik, Lauren A. Vanderlinden, Debashis Ghosh, Mariah Z. Leivo, Donna E. Hansel, Dan Theodorescu Tags: Molecular and Cellular Pathobiology Source Type: research
Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/{beta}-Catenin Activation
In this study, we conducted a DNA methylome analysis of bone marrow–derived stromal cells from myelodysplastic syndrome (MDS) patients and observed widespread aberrant cytosine hypermethylation occurring preferentially outside CpG islands. Stroma derived from 5-azacytidine–treated patients lacked aberrant methylation and DNMTi treatment of primary MDS stroma enhanced its ability to support erythroid differentiation. An integrative expression analysis revealed that the WNT pathway antagonist FRZB was aberrantly hypermethylated and underexpressed in MDS stroma. This result was confirmed in an independent set of sorted, p...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Tushar D. Bhagat, Si Chen, Matthias Bartenstein, A. Trevor Barlowe, Dagny Von Ahrens, Gaurav S. Choudhary, Patrick Tivnan, Elianna Amin, A. Mario Marcondes, Mathijs A. Sanders, Remco M. Hoogenboezem, Suman Kambhampati, Nandini Ramachandra, Iaonnis Mantzar Tags: Molecular and Cellular Pathobiology Source Type: research
NSD1 Inactivation and SETD2 Mutation Drive a Convergence toward Loss of Function of H3K36 Writers in Clear Cell Renal Cell Carcinomas
Extensive dysregulation of chromatin-modifying genes in clear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the ...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Xiaoping Su, Jianping Zhang, Roger Mouawad, Eva Comperat, Morgan Roupret, Frederick Allanic, Jerome Parra, Marc–Olivier Bitker, Erika J. Thompson, Banumathy Gowrishankar, Jane Houldsworth, John N. Weinstein, Jorg Tost, Bradley M. Broom, David Khayat Tags: Molecular and Cellular Pathobiology Source Type: research
CIB2 Negatively Regulates Oncogenic Signaling in Ovarian Cancer via Sphingosine Kinase 1
Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subseque...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Wenying Zhu, Kate E. Jarman, Noor A. Lokman, Heidi A. Neubauer, Lorena T. Davies, Briony L. Gliddon, Houng Taing, Paul A.B. Moretti, Martin K. Oehler, Melissa R. Pitman, Stuart M. Pitson Tags: Molecular and Cellular Pathobiology Source Type: research
Spi-B-Mediated Silencing of Claudin-2 Promotes Early Dissemination of Lung Cancer Cells from Primary Tumors
Dissociation from epithelial sheets and invasion through the surrounding stroma are critical early events during epithelial cancer metastasis. Here we find that a lymphocyte lineage–restricted transcription factor, Spi-B, is frequently expressed in human lung cancer tissues. The Spi-B–expressing cancer cells coexpressed vimentin but repressed E-cadherin and exhibited invasive behavior. Increased Spi-B expression was associated with tumor grade, lymphatic metastasis, and short overall survival. Mechanistically, Spi-B disrupted intercellular junctions and enhanced invasiveness by reconfiguring the chromatin structure of ...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Wei Du, Xing Xu, Qing Niu, Xuexi Zhang, Yiliang Wei, Ziqiao Wang, Wei Zhang, Jun Yan, Yongxin Ru, Zheng Fu, Xiaobo Li, Yuan Jiang, Zhenyi Ma, Zhenfa Zhang, Zhi Yao, Zhe Liu Tags: Molecular and Cellular Pathobiology Source Type: research
Nrf2 Mutagenic Activation Drives Hepatocarcinogenesis
Nrf2, a master regulator of oxidative stress, is considered a prominent target for prevention of hepatocellular carcinoma (HCC), one of the leading causes of cancer-related deaths worldwide. Here we report that Nrf2-deficient mice resisted diethylnitrosamine (DEN)-induced hepatocarcinogenesis without affecting P450-mediated metabolic activation of DEN. Nrf2 expression, nuclear translocation, and transcriptional activity were enhanced in liver tumors. Overactivated Nrf2 was required for hepatoma growth in DEN-induced HCC. Following DEN treatment, Nrf2 genetic disruption reduced expression of pentose phosphate pathway-relate...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Hoang Kieu Chi Ngo, Do-Hee Kim, Young-Nam Cha, Hye-Kyung Na, Young-Joon Surh Tags: Molecular and Cellular Pathobiology Source Type: research
Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells
Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Josephina Sampson, Laura O'Regan, Martin J.S. Dyer, Richard Bayliss, Andrew M. Fry Tags: Molecular and Cellular Pathobiology Source Type: research
Huwe1 Sustains Normal Ovarian Epithelial Cell Transformation and Tumor Growth through the Histone H1.3-H19 Cascade
Ubiquitination-directed protein degradation is important in many cancers for tumor initiation and maintenance, and E3 ligases containing HECT domains are emerging as new therapeutic targets. In contrast to many other E3 ligases, the role of HUWE1 in ovarian cancer where HUWE1 is dysregulated has been unclear. Here we report that genetic deletion of Huwe1 in the mouse inhibits transformation of ovary surface epithelium cells without significantly affecting cell survival and apoptosis, and that Huwe1 deletion after tumors have been initiated inhibits tumor growth. In Huwe1-deficient cells, expression of histone H1.3 increase...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Dong Yang, Bin Sun, Xiaohong Zhang, Daomei Cheng, Xiaoping Yu, Lanzhen Yan, Lei Li, Sanqi An, Hua Jiang, Anna Lasorella, Antonio Iavarone, Shu Zhang, Fangdong Zou, Xudong Zhao Tags: Molecular and Cellular Pathobiology Source Type: research
The Damaging Effect of Passenger Mutations on Cancer Progression
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution; most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established. To assess this, we introduced increasing passenger loads into human...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Christopher D. McFarland, Julia A. Yaglom, Jonathan W. Wojtkowiak, Jacob G. Scott, David L. Morse, Michael Y. Sherman, Leonid A. Mirny Tags: Molecular and Cellular Pathobiology Source Type: research
Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency
In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficie...
Source: Cancer Research - September 14, 2017 Category: Cancer & Oncology Authors: Helen Davies, Sandro Morganella, Colin A. Purdie, Se Jin Jang, Elin Borgen, Hege Russnes, Dominik Glodzik, Xueqing Zou, Alain Viari, Andrea L. Richardson, Anne–Lise Borresen–Dale, Alastair Thompson, Jorunn E. Eyfȷord, Gu Kong, Michael R Tags: Priority Report Source Type: research
