Epigenetic mechanisms mediate heritable control of cell identity in normal cells and cancer. We sought to identify epigenetic regulators driving the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal human cancers. We found that KDM2B (also known as Ndy1, FBXL10, and JHDM1B), an H3K36 histone demethylase implicated in bypass of cellular senescence and somatic cell reprogramming, is markedly overexpressed in human PDAC, with levels increasing with disease grade and stage, and highest expression in metastases. KDM2B silencing abrogated tumorigenicity of PDAC cell lines exhibiting loss of epithelial differentiation, whereas KDM2B overexpression cooperated with KrasG12D to promote PDAC formation in mouse models. Gain- and loss-of-function experiments coupled to genome-wide gene expression and ChIP studies revealed that KDM2B drives tumorigenicity through 2 different transcriptional mechanisms. KDM2B repressed developmental genes through cobinding with Polycomb group (PcG) proteins at transcriptional start sites, whereas it activated a module of metabolic genes, including mediators of protein synthesis and mitochondrial function, cobound by the MYC oncogene and the histone demethylase KDM5A. These results defined epigenetic programs through which KDM2B subverts cellular differentiation and drives the pathogenesis of an aggressive subset of PDAC.
Alexandros Tzatsos, Polina Paskaleva, Francesco Ferrari, Vikram Deshpande, Svetlana Stoykova, Gianmarco Contino, Kwok-Kin Wong, Fei Lan, Patrick Trojer, Peter J. Park, Nabeel Bardeesy
Secreted protein acidic and rich in cysteine (SPARC) has been implicated in multiple aspects of human cancer. However, its role in bladder carcinogenesis and metastasis are unclear,with some studies suggesting it may be a promoter and others arguing the opposite. Using a chemical carcinogenesis model in
Neveen Said, Henry F. Frierson, Marta Sanchez-Carbayo, Rolf A. Brekken, Dan Theodorescu
MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre–B cell leukemia transcription factor–interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.
Xiaojie Xu, Zhongyi Fan, Lei Kang, Juqiang Han, Chengying Jiang, Xiaofei Zheng, Ziman Zhu, Huabo Jiao, Jing Lin, Kai Jiang, Lihua Ding, Hao Zhang, Long Cheng, Hanjiang Fu, Yi Song, Ying Jiang, Jiahong Liu, Rongfu Wang, Nan Du, Qinong Ye
Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of
Stefan Thiem, Thomas P. Pierce, Michelle Palmieri, Tracy L. Putoczki, Michael Buchert, Adele Preaudet, Ryan O. Farid, Chris Love, Bruno Catimel, Zhengdeng Lei, Steve Rozen, Veena Gopalakrishnan, Fred Schaper, Michael Hallek, Alex Boussioutas, Patrick Tan, Andrew Jarnicki, Matthias Ernst
Clear cell sarcoma (CCS) is an aggressive soft tissue malignant tumor characterized by a unique t(12;22) translocation that leads to the expression of a chimeric
Kazunari Yamada, Takatoshi Ohno, Hitomi Aoki, Katsunori Semi, Akira Watanabe, Hiroshi Moritake, Shunichi Shiozawa, Takahiro Kunisada, Yukiko Kobayashi, Junya Toguchida, Katsuji Shimizu, Akira Hara, Yasuhiro Yamada
Instability in the composition of gut bacterial communities (dysbiosis) has been linked to common human intestinal disorders, such as Crohn’s disease and colorectal cancer. Here, we show that dysbiosis caused by
Aurélie Couturier-Maillard, Thomas Secher, Ateequr Rehman, Sylvain Normand, Adèle De Arcangelis, Robert Haesler, Ludovic Huot, Teddy Grandjean, Aude Bressenot, Anne Delanoye-Crespin, Olivier Gaillot, Stefan Schreiber, Yves Lemoine, Bernhard Ryffel, David Hot, Gabriel Nùñez, Grace Chen, Philip Rosenstiel, Mathias Chamaillard
Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of
Michael A. Augello, Craig J. Burd, Ruth Birbe, Christopher McNair, Adam Ertel, Michael S. Magee, Daniel E. Frigo, Kari Wilder-Romans, Mark Shilkrut, Sumin Han, Danielle L. Jernigan, Jeffry L. Dean, Alessandro Fatatis, Donald P. McDonnell, Tapio Visakorpi, Felix Y. Feng, Karen E. Knudsen
Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named “
Roel G.W. Verhaak, Pablo Tamayo, Ji-Yeon Yang, Diana Hubbard, Hailei Zhang, Chad J. Creighton, Sian Fereday, Michael Lawrence, Scott L. Carter, Craig H. Mermel, Aleksandar D. Kostic, Dariush Etemadmoghadam, Gordon Saksena, Kristian Cibulskis, Sekhar Duraisamy, Keren Levanon, Carrie Sougnez, Aviad Tsherniak, Sebastian Gomez, Robert Onofrio, Stacey Gabriel, Lynda Chin, Nianxiang Zhang, Paul T. Spellman, Yiqun Zhang, Rehan Akbani, Katherine A. Hoadley, Ari Kahn, Martin Köbel, David Huntsman, Robert A. Soslow, Anna Defazio, Michael J. Birrer, Joe W. Gray, John N. Weinstein, David D. Bowtell, Ronny Drapkin, Jill P. Mesirov, Gad Getz, Douglas A. Levine, Matthew Meyerson
Late-stage breast cancer metastasis is driven by dysregulated TGF-β signaling, but the underlying molecular mechanisms have not been fully elucidated. We attempted to recapitulate tumor and metastatic microenvironments via the use of biomechanically compliant or rigid 3D organotypic cultures and combined them with global microRNA (miR) profiling analyses to identify miRs that were upregulated in metastatic breast cancer cells by TGF-β. Here we establish miR-181a as a TGF-β–regulated “metastamir” that enhanced the metastatic potential of breast cancers by promoting epithelial-mesenchymal transition, migratory, and invasive phenotypes. Mechanistically, inactivation of miR-181a elevated the expression of the proapoptotic molecule Bim, which sensitized metastatic cells to anoikis. Along these lines, miR-181a expression was essential in driving pulmonary micrometastatic outgrowth and enhancing the lethality of late-stage mammary tumors in mice. Finally, miR-181a expression was dramatically and selectively upregulated in metastatic breast tumors, particularly triple-negative breast cancers, and was highly predictive for decreased overall survival in human breast cancer patients. Collectively, our findings strongly implicate miR-181a as a predictive biomarker for breast cancer metastasis and patient survival, and consequently, as a potential therapeutic target in metastatic breast cancer.
Molly A. Taylor, Khalid Sossey-Alaoui, Cheryl L. Thompson, David Danielpour, William P. Schiemann
High-grade gliomas (HGGs) are incurable brain tumors that are characterized by the presence of glioma-initiating cells (GICs). GICs are essential to tumor aggressiveness and retain the capacity for self-renewal and multilineage differentiation as long as they reside in the perivascular niche. ID proteins are master regulators of stemness and anchorage to the extracellular niche microenvironment, suggesting that they may play a role in maintaining GICs. Here, we modeled the probable therapeutic impact of ID inactivation in HGG by selective ablation of Id in tumor cells and after tumor initiation in a new mouse model of human mesenchymal HGG. Deletion of 3 Id genes induced rapid release of GICs from the perivascular niche, followed by tumor regression. GIC displacement was mediated by derepression of Rap1gap and subsequent inhibition of RAP1, a master regulator of cell adhesion. We identified a signature module of 5 genes in the ID pathway, including RAP1GAP, which segregated 2 subgroups of glioma patients with markedly different clinical outcomes. The model-informed survival analysis together with genetic and functional studies establish that ID activity is required for the maintenance of mesenchymal HGG and suggest that pharmacological inactivation of ID proteins could serve as a therapeutic strategy.
Francesco Niola, Xudong Zhao, Devendra Singh, Ryan Sullivan, Angelica Castano, Antonio Verrico, Pietro Zoppoli, Dinorah Friedmann-Morvinski, Erik Sulman, Lindy Barrett, Yuan Zhuang, Inder Verma, Robert Benezra, Ken Aldape, Antonio Iavarone, Anna Lasorella