A5037062908- Lung Cancer Research Studies
- Glycosylation and Glycoproteins Research
- Cancer Genomics and Diagnostics
- RNA modifications and cancer
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Infectious Diseases and Mycology
- Advanced Breast Cancer Therapies
- Neuroendocrine Tumor Research Advances
- Genomics and Chromatin Dynamics
- Cancer-related Molecular Pathways
- Cancer-related molecular mechanisms research
- Cancer, Hypoxia, and Metabolism
- Epigenetics and DNA Methylation
- interferon and immune responses
- Breast Cancer Treatment Studies
- Medical Imaging Techniques and Applications
- Breast Lesions and Carcinomas
- Head and Neck Cancer Studies
- Lung Cancer Treatments and Mutations
- Ubiquitin and proteasome pathways
- Prostate Cancer Treatment and Research
- Microtubule and mitosis dynamics
- Medical Imaging and Pathology Studies
- Radiopharmaceutical Chemistry and Applications
- Cancer Cells and Metastasis
Jikei University School of Medicine
2018-2025
Dana-Farber Cancer Institute
2019-2024
Harvard University
2019-2024
The Jikei University Hospital
2020
Jikei University Kashiwa hospital
2019
St. Luke's International Hospital
2013-2018
Saitama University
2010
Abstract Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein overexpressed in castration-resistant (CRPC) and NEPC, but its specific role unknown. Here, we demonstrate that upregulation of androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling induces the neural BRN2 transcription factor. activates a MYC→BRN2 pathway association induction MYCN, EZH2 NE differentiation markers (ASCL1, AURKA...
The polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. present work demonstrates induces BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. functional significance MUC1-C→PBAF pathway supported demonstrating involvement associating with...
Background Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness TNBCs to ICIs is lack functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C mouse transgenic TNBC model increases cytotoxic CD8+ T cells (CTLs),...
Abstract The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. oncogenic MUC1-C protein promotes lineage plasticity the progression neuroendocrine cancer (NEPC), however, there no known association between BAF. We report here that binds directly E2F1 transcription MUC1-C→E2F1 pathway induces expression embryonic stem cell–specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, BAF170...
Abstract The MUC1 gene evolved in mammals for adaptation of barrier tissues response to infections and damage. Paraspeckles are nuclear bodies formed on the NEAT1 lncRNA loss homeostasis. There is no known intersection with or paraspeckles. Here, we demonstrate that MUC1-C subunit plays an essential role regulating expression. activates induction NEAT1_1 NEAT1_2 isoforms by NF-κB- MYC-mediated mechanisms. MUC1-C/MYC signaling also induces expression SFPQ, NONO FUS RNA binding proteins (RBPs)...
The NuRD chromatin remodeling and deacetylation complex, which includes MTA1, MBD3, CHD4, HDAC1 among other components, is of importance for development cancer progression. oncogenic mucin 1 (MUC1) C-terminal subunit (MUC1-C) protein activates EZH2 BMI1 in the epigenetic reprogramming triple-negative breast (TNBC). However, there no known link between MUC1-C complexes. Here, we showed that binds directly to MYC HLH-LZ domain identified a previously unrecognized MUC1-C→MYC pathway regulates...
Colitis is associated with the development of colorectal cancer (CRC) by largely undefined mechanisms that are critical for understanding link between inflammation and cancer. Intestinal stem cells (ISCs) marked leucine-rich repeat–containing G protein–coupled receptor 5 (LGR5) expression importance in both inflammatory response to colitis progression colitis-associated colon (CACC). Here, we report human mucin 1–transgenic (MUC1-transgenic) mouse models CACC, targeting MUC1-C oncogenic...
The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. present work demonstrates that is necessary for expression IFNGR1 and activation the type II interferon-gamma (IFN-γ) pathway. We show MUC1-C→ARID1A/BAF signaling induces transcription MUC1-C-induced NuRD complex suppresses FBXW7 stabilizing protein. were also downstream STAT1 IRF1 factors. further demonstrate PBRM1/PBAF are IRF1-induced (i) IDO1,...
Abstract The oncogenic MUC1-C protein promotes dedifferentiation of castrate-resistant prostate cancer (CRPC) and triple-negative breast (TNBC) cells. Chromatin remodeling is critical for the stem cell (CSC) state; however, there no definitive evidence that regulates chromatin accessibility thereby expression stemness-associated genes. We demonstrate drives global changes in architecture CRPC TNBC Our results show induces differentially accessible regions (DAR) across their genomes, which...
The MUC1-C protein evolved in mammals to protect barrier tissues from loss of homeostasis; however, promotes oncogenesis association with chronic inflammation. Aberrant expression cancers has been linked depletion and dysfunction T cells the tumor microenvironment. In contrast, there is no known involvement regulation natural killer (NK) cell function.Targeting genetically pharmacologically cancer was performed assess effects on intracellular surface MHC class I chain-related polypeptide A...
Inhibition of CDK4/6 kinases has led to improved outcomes in breast cancer. Nevertheless, only a minority patients experience long-term disease control. Using large, clinically annotated cohort with metastatic hormone receptor-positive (HR+) cancer, we identify TP53 loss (27.6%) and MDM2 amplification (6.4%) be associated lack Human cancer models reveal that p53 does not alter activity or G1 blockade but instead promotes drug-insensitive p130 phosphorylation by CDK2. The persistence...
Tumor-infiltrating lymphocyte (TIL) scoring in tumor specimens has gained increasing attention determining patients who are likely to benefit from immunotherapies. However, the histological evaluation methods of TILs breast cancer remain limited. This study aimed assess four components lymphocytic reaction and overall score (L-score) used colorectal cancer, investigate its association with clinicopathological factors, examine effect on postoperative mortality using 231 invasive cancers...
Abstract The polybromo-1 (PBRM1) chromatin-targeting subunit of the SWI/SNF PBAF chromatin remodeling complex drives DNA damage resistance and immune evasion in certain cancer cells through mechanisms that remain unclear. STAT1 IRF1 are essential effectors type I II IFN pathways. Here, we report MUC1-C is necessary for PBRM1 expression it forms a nuclear with triple-negative breast (TNBC) cells. Analysis global transcriptional (RNA-seq) accessibility (ATAC-seq) profiles further demonstrated...
Abstract Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated the inflammatory NF-κB pathway cells. There no known involvement of regulation COMPASS family H3K4 methyltransferases. We find regulates (i) bulk methylation levels, and (ii) SET1A/SETD1A WDR5 genes an NF-κB-mediated mechanism. importance regulating SET1A complex supported demonstration drive expression FOS, ATF3 other AP-1 members....
The MUC1-C apical transmembrane protein is activated in the acute response of epithelial cells to inflammation. However, chronic activation promotes cancer progression, emphasizing importance as a target for treatment. We report here that necessary intrinsic expression RIG-I, MDA5 and cGAS cytosolic nucleotide pattern recognition receptors (PRRs) cGAS-stimulator IFN genes (STING) triple-negative breast (TNBC) cells. Consistent with inducing PRR/STING axis, drives IFN-β production type I...
Abstract Merkel cell carcinoma (MCC) is an aggressive malignancy with neuroendocrine (NE) features, limited treatment options, and a lack of druggable targets. There no reported involvement the MUC1-C oncogenic protein in MCC progression. We show here that broadly expressed MCCs at higher levels polyomavirus (MCPyV)-positive (MCCP) relative to MCPyV-negative (MCCN) tumors. Our results further demonstrate MCCP, as well MCCN, lines regulates common sets signaling pathways related RNA...
Abstract Small cell lung cancer (SCLC) is a recalcitrant malignancy defined by subtypes on the basis of differential expression ASCL1, NEUROD1, and POU2F3 transcription factors. The MUC1-C protein activated in pulmonary epithelial cells exposure to environmental carcinogens promotes oncogenesis; however, there no known association between SCLC. We report that expressed classic neuroendocrine (NE) SCLC-A, variant NE SCLC-N non-NE SCLC-P activates MYC pathway these subtypes. In SCLC...
Activation of the MUC1-C protein promotes lineage plasticity, epigenetic reprogramming, and cancer stem cell (CSC) state. The present studies performed on enriched populations triple-negative breast (TNBC) CSCs demonstrate that is essential for integrating activation glycolytic pathway genes with self-renewal tumorigenicity. further integrates suppression mitochondrial DNA (mtDNA) encoding components Complexes I-V. repression mtDNA explained by MUC1-C-mediated (i) downregulation...
Abstract Pancreatic ductal adenocarcinomas (PDAC) and poorly differentiated pancreatic neuroendocrine (NE) carcinomas are KRAS mutant malignancies with a potential common cell of origin. PDAC ductal, but not NE, lineage traits have been associated cell-intrinsic activation interferon (IFN) pathways. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1-C), which evolved to protect mammalian epithelia from loss homeostasis, is aberrantly overexpressed in tumors lines. We show...
Abstract The MUC1-C protein is aberrantly expressed in adenocarcinomas of epithelial barrier tissues and contributes to their progression. Less known about involvement the pathogenesis squamous cell carcinomas (SCCs). Here, we report that MUC1 gene upregulated advanced head neck SCCs (HNSCCs). Studies HNSCC lines demonstrate subunit regulates expression (i) RIG-I MDA5 pattern recognition receptors, (ii) STAT1 interferon (IFN) regulatory factors, (iii) downstream IFN-stimulated genes (ISGs)....