Abstract:
:Inhibition of tumor suppressive signaling is linked to cancer progression, metastasis and epithelial-mesenchymal transition (EMT). Transforming growth factor-β1 (TGF-β)/Smad signaling plays an important role in tumor suppression. Kruppel-like-factor 17 (KLF17) is a negative regulator of metastasis and EMT. However, underlying mechanisms leading to tumor suppressive and anti-metastatic function of KLF17 still remains unknown. Here, we show that KLF17 plays an integral role in potentiating TGF-β/Smad signaling via Smad3-dependent pathway to suppress tumor progression. Intriguingly, TGF-β/Smad3 signaling induces KLF17 expression, generating a positive feedback loop. TGF-β/Smad3-KLF17 loop is critical for anti-metastasis and tumor inhibition in cancer cells. Mechanistically, silencing KLF17 reduced Smad3-DNA complex formation on Smad binding element (SBE) and affects the expression of TGF-β/Smad target genes. Moreover, KLF17 alters Smad3 binding pattern on chromatin. KLF17 regulates TGF-β target genes that are Smad3-dependent. Smad3 and KLF17 physically interact with each other via KLF17 responsive elements/SBE region. Intriguingly, TGF-β stimulates the recruitment of KLF17 on chromatin to subsets of metastasis-associated genes. Functionally, depletion of KLF17 enhanced tumorigenic features in cancer cells. KLF17 is critical for full cytostatic function of TGF-β/Smad signaling. Clinically, KLF17 expression significantly decreases during advance HCC. KLF17 shows positive correlation with Smad3 levels in cancer samples. Our data shows that enhance KLF17 activity has important therapeutic implications for targeted-therapies aimed at TGF-β/Smad3 pathway. These findings define novel mechanism by which TGF-β/Smad-KLF17 pathway mutually affect each other during cancer metastasis, provide a new model of regulation of TGF-β/Smad signaling by KLF17 and defines new insights into anti-metastatic function of KLF17.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
Ali A,Zhang P,Liangfang Y,Wenshe S,Wang H,Lin X,Dai Y,Feng XH,Moses R,Wang D,Li X,Xiao Jdoi
10.1038/cddis.2015.48subject
Has Abstractpub_date
2015-03-12 00:00:00pages
e1681issn
2041-4889pii
cddis201548journal_volume
6pub_type
杂志文章abstract::Bone loss in postmenopausal osteoporosis is induced chiefly by an imbalance of bone-forming osteoblasts and bone-resorbing osteoclasts. Salubrinal is a synthetic compound that inhibits de-phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Phosphorylation of eIF2α alleviates endoplasmic reticu...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-2159-z
更新日期:2019-12-04 00:00:00
abstract::SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergi...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.74
更新日期:2016-04-07 00:00:00
abstract::An increasing interest in liver cancer stemness arises owing to its aggressive behavior and poor prognosis. CD133, a widely known liver cancer stem cell marker, plays critical roles in the maintenance of liver cancer stemness. Thus, exploring the regulatory mechanism of CD133 expression is significant. In the present ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1712-0
更新日期:2019-06-13 00:00:00
abstract::Impaired synaptic plasticity and neuron loss are hallmarks of Alzheimer's disease and vascular dementia. Here, we found that chronic brain hypoperfusion (CBH) by bilateral common carotid artery occlusion (2VO) decreased the total length, numbers and crossings of dendrites and caused neuron death in rat hippocampi and ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2017.243
更新日期:2017-06-01 00:00:00
abstract::Estrogen receptor-alpha positive (ER(+)) breast cancers comprise the majority of human breast cancers, but molecular mechanisms underlying this subtype of breast cancers remain poorly understood. Here, we show that ER(+) mammary luminal tumors arising in Tip30(-/-)MMTV-Neu mice exhibited increased enrichment of lumina...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.224
更新日期:2014-05-22 00:00:00
abstract::Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell de...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.214
更新日期:2016-08-04 00:00:00
abstract::Aberrant regulation of cholesterol homeostasis is associated with obesity as well as multiple types of cancer. However, the mechanism behind these is largely missing. Here, we show that microRNA (miRNA)-128-2 is not only a pro-apoptotic microRNA but it also alters the expression of genes involved in cellular cholester...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.301
更新日期:2013-08-29 00:00:00
abstract::Homeodomain-interacting protein kinase 2 (HIPK2) is a multitalented coregulator of an increasing number of transcription factors and cofactors involved in cell death and proliferation in several organs and systems. As Hipk2(-/-) mice show behavioral abnormalities consistent with cerebellar dysfunction, we investigated...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2015.298
更新日期:2015-12-03 00:00:00
abstract::SAM and SH3 domain-containing 1 (SASH1), a scaffold protein, is regarded as a tumor suppressor. Recent studies have verified the decreased expression of SASH1 in many tumors. Our previous clinical investigation found that SASH1 was widely expressed in normal brain tissues but reduced or absent in glioma tissues. Howev...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1645-7
更新日期:2019-05-28 00:00:00
abstract::Noncoding RNAs plays an important role in hepatocellular carcinoma (HCC). Here, we show that miR-124 was downregulated in HCC tissues and that the ectopic expression of miR-124 inhibited the proliferation and migration of HCC cells. We proposed that aquaporin 3 (AQP3) is a direct target of miR-124. AQP3 was upregulate...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-017-0204-3
更新日期:2018-02-07 00:00:00
abstract::Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inver...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0564-3
更新日期:2018-05-01 00:00:00
abstract::Thyroid hormone (TH) plays a crucial role in neurodevelopment, but its function and specific mechanisms remain unclear after traumatic brain injury (TBI). Here we found that treatment with triiodothyronine (T3) ameliorated the progression of neurological deficits in mice subjected to TBI. The data showed that T3 reduc...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-02836-9
更新日期:2020-08-09 00:00:00
abstract::Cell migration plays pivotal roles in many biological processes; however, its underlying mechanism remains unclear. Here, we find that NudC-like protein 2 (NudCL2), a cochaperone of heat shock protein 90 (Hsp90), modulates cell migration by stabilizing both myosin-9 and lissencephaly protein 1 (LIS1). Either knockdown...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-02739-9
更新日期:2020-07-14 00:00:00
abstract::The link between tendon stem/progenitor cells (TSPCs) senescence and tendon aging has been well recognized. However, the cellular and molecular mechanisms of TSPCs senescence are still not fully understood. In present study, we investigated the role of Aquaporin 1 (AQP1) in TSPCs senescence. We showed that AQP1 expres...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-020-2386-3
更新日期:2020-03-18 00:00:00
abstract::Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.104
更新日期:2016-04-28 00:00:00
abstract::Epigenetic alteration of tumor suppression gene is one of the most significant indicators in human esophageal squamous cell carcinoma (ESCC). In this study, we identified a novel ESCC hypermethylation biomarker ZNF132 by integrative computational analysis to comprehensive genome-wide DNA methylation microarray dataset...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1236-z
更新日期:2018-12-18 00:00:00
abstract::The mechanism by which tumor-associated macrophages (TAMs) affect cancer progression is not fully understood. This study developed a microfluidic-based co-culture device to mimic the tumor microenvironment to assess TAM effects on invasion and metastasis in NSCLC. The results showed lung carcinoma cells could cause ma...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1618-x
更新日期:2019-05-16 00:00:00
abstract::The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pat...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2016.443
更新日期:2017-01-05 00:00:00
abstract::Copious evidence demonstrates the crucial role of Rho GTPase-activating proteins in human malignancies. The downregulation of Rho GTPase-activating protein 15 (ARHGAP15), a Rac1-specific GAP, has been observed in glioma and pancreatic ductal adenocarcinoma. The present study explored the expression in colorectal cance...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0707-6
更新日期:2018-06-04 00:00:00
abstract::The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP and anabolic substrates at distinct phases of the cell cycle. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators of glucose metabolism via their synt...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.292
更新日期:2014-07-17 00:00:00
abstract::Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) poses a serious threat to the world's public health yet without a cure. Certain JEV-infected neural cells express a subset of previously identified intrinsic antiviral interferon stimulated genes (ISGs), indicating brain cells retain autonomous ant...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0763-y
更新日期:2018-06-18 00:00:00
abstract::Chemotherapy is a standard treatment for non-small-cell lung cancer (NSCLC). However, the dose-limiting toxicity of drugs and the development of chemoresistance are major clinical challenges to successful management of NSCLC. Asian traditional medicine is gaining global attention as a non-toxic alternative to chemothe...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0277-7
更新日期:2018-02-14 00:00:00
abstract::Autophagy has emerged as a critical pathway in tumor development. S100A4 plays important roles in tumor metastasis, but its role in regulating autophagy has not been well characterized. In this study, we found that S100A4 was significantly upregulated in lung adenocarcinoma tissues. Clinical investigation demonstrated...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-0319-1
更新日期:2018-02-15 00:00:00
abstract::Diffusely infiltrating gliomas are among the most prognostically discouraging neoplasia in human. Temozolomide (TMZ) in combination with radiotherapy is currently used for the treatment of glioblastoma (GBM) patients, but less than half of the patients respond to therapy and chemoresistance develops rapidly. Epigeneti...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.245
更新日期:2014-06-05 00:00:00
abstract::Protein tyrosine kinase 7 (PTK7) and cancer-associated fibroblasts (CAFs) play important roles in cancer stemness, respectively. However, little is known about interaction between CAFs and PTK7 in cancers. In this study, we showed that PTK7 was significantly correlated with the Wnt/β-Catenin pathway and aggressive cli...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-018-1116-6
更新日期:2018-10-22 00:00:00
abstract::β-Catenin has been widely implicated in the regulation of mammalian development and cellular homeostasis. However, the mechanisms by which Wnt/β-catenin signaling components regulate physiological events during brain development remain undetermined. Inactivation of glycogen synthase kinase (GSK)-3β leads to β-catenin ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.439
更新日期:2014-10-16 00:00:00
abstract::Global cerebral ischemia/reperfusion (I/R) facilitates the activation of procaspase-3 and promotes apoptosis in hippocampus. But the mechanisms have remained uncharacterized. Protein S-nitrosylation and denitrosylation is an important reversible posttranslational modification, which is a common mechanism in signal tra...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2013.299
更新日期:2013-08-15 00:00:00
abstract::Breast cancer is the most significant threat to female health. Breast cancer metastasis is the major cause of mortality in breast cancer patients. To fully unravel the molecular mechanisms that underlie the breast cancer cell metastasis is critical for developing strategies to improve survival and prognosis in breast ...
journal_title:Cell death & disease
pub_type: 杂志文章,评审
doi:10.1038/s41419-020-02954-4
更新日期:2020-09-14 00:00:00
abstract::Characterized by their slow adhering property, skeletal muscle myogenic progenitor cells (MPCs) have been widely utilized in skeletal muscle tissue engineering for muscle regeneration, but with limited efficacy. Skeletal muscle regeneration is regulated by various cell types, including a large number of rapidly adheri...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/s41419-019-1647-5
更新日期:2019-06-03 00:00:00
abstract::Intestinal epithelial cells (IECs) not only have a critical function in the absorption of nutrients, but also act as a physical barrier between our body and the outside world. Damage and death of the epithelial cells lead to the breakdown of this barrier function and inflammation due to access of the immune system to ...
journal_title:Cell death & disease
pub_type: 杂志文章
doi:10.1038/cddis.2014.183
更新日期:2014-05-15 00:00:00