Function and regulation of Rab GTPases in cancers.

The Rab small GTPases are characterized by the distinct intracellular localization and modulate various endocytic, transcytic and exocytic transport pathways. Rab proteins function as scaffolds that connect signaling pathways and intracellular membrane trafficking processes through the recruitment of effectors, such as tethering factors, phosphatases, motors and kinases. In different cancers, Rabs play as either an onco-protein or a tumor suppressor role, highly dependending on the context. The molecular mechanistic research has revealed that Rab proteins are involved in cancer progression through influences on migration, invasion, metabolism, exosome secretion, autophagy, and drug resistance of cancer cells. Therefore, targeting Rab GTPases to recover the dysregulated vesicle transport systems may provide potential strategy to restrain cancer progression. In this review, we discuss the regulation of Rab protein level and activity in modulating pathways involved in tumor progression, and propose that Rab proteins may serve as a prognostic factor in different cancers.

ACKR3 orchestrates Hedgehog signaling to promote renal cell carcinoma progression.

Renal cell carcinoma (RCC) is the second commonest urological malignant neoplasm and mortality rate of patients with RCC appears to be increasing each year. Thus, further understanding of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. Here, we report that atypical chemokine receptor 3 (ACKR3) orchestrates the Hedgehog (Hh)-GLI1 signaling to promote RCC progression. The expression of ACKR3 is elevated in RCC tissues, which is associated with malignant and clinical outcomes of RCC, and ACKR3 expression is positively correlated with GLI1 expression in RCC tissues. Mechanically, Hh promotes RCC progression through GLI1-mediated ACKR3 transcription by the directly binding of GLI1 to ACKR3 gene, while CXCL12-ACKR3 axis simultaneously enhances Hh activation via the binding of ACKR3 to Smoothened (SMO), a receptor in Hh pathway, resulting in the upregulation of SMO phosphorylation that potentiates downstream signal activity and consequently contributes to RCC progression. Thus, our findings may provide with the evidence of developing a novel treatment method with specific target for RCC.

ALKBH1 contributes to renal cell carcinoma progression by reducing N6-methyladenine of GPR137.

BACKGROUND: Renal cell carcinoma (RCC) accounts for approximately 4% of all adult malignancies with high mortality worldwide. Although conventional chemotherapy and radiotherapy treatment has been applied for RCC in clinic, the mortality rate of patients is increasing each year, and patients with metastatic RCC are still suffering from poor prognosis. Thus, further investigation of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. METHODS: Total of 10 pairs of RCC tissues and adjacent nontumor tissues were collected for examination of ALKBH1 and GPR137 expression. The correlations between ALKBH1 and GPR137 expression in RCC patient were assessed by GEPIA online tool and were analyzed using auto best cutoff. The human RCC cell lines Caki-1, 786-O, ACHN, Osrc2, A498, and 769-P, were used for mechanistic investigation. RESULTS: Here, we report that the expression of AlkB homologue 1 (ALKBH1) is upregulated in RCC tissues, which is correlated with G-protein-coupled receptor 137 (GPR137) expression. The elevated expression of ALKBH1 is associated with RCC cell malignant characteristics, including cell proliferation and movement (migration and invasion). Mechanistic investigation further reveals that ALKBH1 reduces m6 A levels of GPR137 mRNA in RCC cells, which upregulates GPR137 mRNA levels, resulting in the increased GPR137 protein expression subsequently and the enhanced RCC cell biological actions consequently. In contrast, the suppression of GPR137 effectively alleviates the ALKBH1-induced malignancies of RCC cells. CONCLUSION: Our results indicate that ALKBH1-GPR137 axis might be used as a potential therapeutic target in RCC, contributing to finding new prognostic biomarkers for RCC at an early stage.

Micro-RNAs in Human Placenta: Tiny Molecules, Immense Power.

Micro-RNAs (miRNAs) are short non-coding single-stranded RNAs that modulate the expression of various target genes after transcription. The expression and distribution of kinds of miRNAs have been characterized in human placenta during different gestational stages. The identified miRNAs are recognized as key mediators in the regulation of placental development and in the maintenance of human pregnancy. Aberrant expression of miRNAs is associated with compromised pregnancies in humans, and dysregulation of those miRNAs contributes to the occurrence and development of related diseases during pregnancy, such as pre-eclampsia (PE), fetal growth restriction (FGR), gestational diabetes mellitus (GDM), recurrent miscarriage, preterm birth (PTB) and small-for-gestational-age (SGA). Thus, having a better understanding of the expression and functions of miRNAs in human placenta during pregnancy and thereby developing novel drugs targeting the miRNAs could be a potentially promising method in the prevention and treatment of relevant diseases in future. Here, we summarize the current knowledge of the expression pattern and function regulation of miRNAs in human placental development and related diseases.

MicroRNA-3935 promotes human trophoblast cell epithelial-mesenchymal transition through tumor necrosis factor receptor-associated factor 6/regulator of G protein signaling 2 axis.

BACKGROUND: Insufficient migration and invasion during trophoblast epithelial-mesenchymal transition (EMT) results in the occurrence and development of preeclampsia (PE), and our previous study has screened 52 miRNAs, whose expression levels are altered in the placental samples from PE patients, compared with the normal group. Among those, miR-3935 is one of the miRNAs being most significantly down-regulated, indicating its involvement in PE. However, the exact effect and molecular mechanisms remain unknown. METHODS: In the present study, we investigate the roles and underlying mechanisms of miR-3935 in trophoblast EMT by use of the human extra-villous trophoblast cell line HTR-8/SVneo as well as human placental tissues and maternal blood samples obtained from 15 women with normal pregnancies and 15 women with PE. Experimental methods include transfection, quantitative reverse transcription-PCR (qRT-PCR), western blot, immunofluorescence staining, dual-luciferase assays, in vitro invasion and migration assays, RNA-Seq analysis, bisulfite sequencing and immunohistochemistry staining. RESULTS: MiR-3935 expression is significantly decreased in both placentas and peripheral blood specimens of PE, and functionally, miR-3935 promotes EMT of trophoblast cells. Mechanistically, TRAF6 is identified to be a direct target of miR-3935 and TRAF6 exerts its negative effect on EMT of trophoblast cells by inhibition of RGS2, which down-regulates the methylation status of promoter of CDH1 gene that encodes E-Cadherin protein through induction of ALKBH1, resulting in increase of E-Cadherin and subsequently insufficient trophoblast EMT. CONCLUSIONS: Together these results uncover a hitherto uncharacterized role of miR-3935/TRAF6/RGS2 axis in the function of human trophoblasts, which may pinpoint the molecular pathogenesis of PE and may be a prognostic biomarker and therapeutic target for such obstetrical diseases as PE.

Rab34 small GTPase is required for Hedgehog signaling and an early step of ciliary vesicle formation in mouse.

The primary cilium is a microtubule-based organelle that protrudes from the cell surface and plays essential roles in embryonic development. Ciliogenesis begins with the successive fusion of preciliary vesicles to form ciliary vesicles, which then dock onto the distal end of the mother centriole. Rab proteins have been linked to cilia formation in cultured cells, but not yet in vivo In the present study, we demonstrate that endocytic recycling protein Rab34 localizes to cilia, and that its mutation results in significant decrease of ciliogenesis in both cultured cells and mice. Rab34 is required for the successive fusion of preciliary vesicles to generate ciliary vesicles and for the migration of the mother centriole from perinuclear region to plasma membrane. We also show that Rab34 mutant mice exhibit polydactyly, and cleft-lip and -palate. These phenotypes are consistent with observations that nonciliated Rab34 mutant cells fail to respond to Hedgehog signaling and that processing of full-length Gli3 to its C-terminally truncated form is reduced in Rab34 mutant embryos. Therefore, Rab34 is required for an early step of ciliary vesicle formation and Hh signaling in vivo This article has an associated First Person interview with the first author of the paper.

Multiplanar imaging properties of Theon sieves.

Greek ladders with diffraction-limited array foci provide a probability to realize array imaging with equal intensity. Here, taking the ancient Theon sequence as an example, we design the optical structure and have measured the focusing properties by digital holography. Then, we verify the multiplanar imaging with different magnifications by experiment. The experimental results agree well with the theoretical analysis. In addition, bi-Fourier planes filtering technology is proposed to solve the problem of crosstalk between different imaging planes to further improve the imaging resolution. Therefore, we can freely design the focal length of the bifocal lens to achieve high-quality imaging at different resolutions. As a kind of amplitude-only diffractive lens, multifocal imaging provides a possibility of application in array biological imaging, ophthalmology, and an optical zoom system.

ARID1A restrains EMT and stemness of ovarian cancer cells through the Hippo pathway.

Genes encoding subunits of SWI/SNF (BAF) chromatin­remodeling complexes are recurrently mutated in a broad array of tumor types, and among the subunits, ARID1A is the most frequent target with mutations. In the present study, it was reported that ARID1A inhibits the epithelial­mesenchymal transition (EMT) and stemness of ovarian cancer cells, accompanied by reduced cell viability, migration and colony formation, suggesting that ARID1A acts as a tumor suppressor in ovarian cancer. Mechanistically, ARID1A exerts its inhibitory effects on ovarian cancer cells by activating the Hippo signaling pathway. Conversely, the overexpression of a gain­of­function transcriptional co­activator with PDZ­binding motif (TAZ) mutant (TAZ­Ser89) effectively reverses the effects induced by ARID1A. In addition, activation of Hippo signaling apparently upregulates ARID1A protein expression, whereas ectopic expression of TAZ­Ser89 results in the markedly decreased ARID1A levels, indicating a feedback of ARID1A­TAZ in regulating ovarian cancer cell EMT and stemness. Thus, the present study uncovered the role of ARID1A through the Hippo/TAZ pathway in modulating EMT and stemness of ovarian cancer cells, and providing with evidence that TAZ inhibitors could effectively prevent initiation and metastasis of ovarian cancer cases where ARID1A is lost or mutated.

GPR137 inactivates Hippo signaling to promote gastric cancer cell malignancy.

As the fifth most common cancer in the world, gastric cancer (GC) ranks as the third major cause of cancer-related death globally. Although surgical resection and chemotherapy still remains the mainstay of potentially curative treatment for GC, chemotherapy resistance and adverse side effects limit their clinical applications. Thus, further investigation of the mechanisms of carcinogenesis in GC and discovery of novel biomarkers is of great concern. We herein report that the elevated expression of GPR137 is correlated with GC. Overexpression of GPR137 potentiates human gastric cancer AGS cell malignancy, including proliferation, migration, invasion, colony formation and xenograft growth in nude mice in vivo, whereas knockout of GPR137 by CRISPR/Cas9 gene editing exerts the opposite effects. Mechanistically, GPR137 could bind to MST, the upstream kinases in Hippo pathway, which disrupts the association of MST with LATS, subsequently activating the transcriptional co-activators, YAP and TAZ, and thereby triggering the target transcription and the alterations in GC cell biological actions consequently. Therefore, our findings may provide with the evidence of developing a potentially novel treatment method with specific target for GC.

Hydrogen-producing microflora and Fe-Fe hydrogenase diversities in seaweed bed associated with marine hot springs of Kalianda, Indonesia.

Microbial fermentation is a promising technology for hydrogen (H(2)) production. H(2) producers in marine geothermal environments are thermophilic and halotolerant. However, no one has surveyed an environment specifically for thermophilic bacteria that produce H(2) through Fe-Fe hydrogenases (H(2)ase). Using heterotrophic medium, several microflora from a seaweed bed associated with marine hot springs were enriched and analyzed for H(2) production. A H(2)-producing microflora was obtained from Sargassum sp., 16S rRNA genes and Fe-Fe H(2)ase diversities of this enrichment were also analyzed. Based on 16S rRNA genes analysis, 10 phylotypes were found in the H(2)-producing microflora showing 90.0-99.5 % identities to known species, and belonged to Clostridia, Gammaproteobacteria, and Bacillales. Clostridia were the most abundant group, and three Clostridia phylotypes were most related to known H(2) producers such as Anaerovorax odorimutans (94.0 % identity), Clostridium papyrosolvens (98.4 % identity), and Clostridium tepidiprofundi (93.1 % identity). For Fe-Fe H(2)ases, seven phylotypes were obtained, showing 63-97 % identities to known Fe-Fe H(2)ases, and fell into four distinct clusters. Phylotypes HW55-3 and HM55-1 belonged to thermophilic and salt-tolerant H(2)-producing Clostridia, Halothermothrix orenii-like Fe-Fe H(2)ases (80 % identity), and cellulolytic H(2)-producing Clostridia, C. papyrosolvens-like Fe-Fe H(2)ases (97 % identity), respectively. The results of both 16S rRNA genes and Fe-Fe H(2)ases surveys suggested that the thermophilic and halotolerant H(2)-producing microflora in seaweed bed of hot spring area represented previously unknown H(2) producers, and have potential application for H(2) production.

Yap1-Usp14 Axis Inhibits Neuronal Mitophagy During Neonatal Hypoxia-Ischemia Encephalopathy by Regulation of Beclin-1 Ubiquitination in Mouse.

Neonatal hypoxic-ischemic encephalopathy (HIE) that results from perinatal cerebral hypoxia-ischemia has become one of the leading causes of acute mortality and chronic disability in infants and children. Despite that neuronal mitophagy and subsequent clearance of damaged neurons exert protective effect, the pathogenesis of HIE and effective treatment strategies for intervention of HIE remain poorly understood. Here, we report that ubiquitin-specific protease 14 (Usp14, a deubiquitinating enzyme) is closely associated with HIE progression by its negative regulation in neuronal mitophagy in mouse. The expression of Usp14 is elevated in both an oxygen-glucose deprivation (OGD) mouse neuronal cell line culture model in vitro and a HIE mouse model in vivo. Mechanistically, OGD treatment activates Hippo signaling that enhances Yap1 phosphorylation levels at Ser-127 but inhibits Yap1 protein level, which potentiates Usp14 transcription and leads to the downregulated ubiquitination at Lys-63 of Beclin-1, a key molecule in autophagy, resulting in the suppressed neuronal mitophagy, subsequent failure in the clearance of damaged neurons, and finally possible dysregulation in brain functions. Thus, our results provide with Usp14 as a novel target and treatment strategy for intervention of HIE, which may help diagnose and treat HIE in clinic.

RGS2 promotes estradiol biosynthesis by trophoblasts during human pregnancy.

Production of estradiol (E2) by the placenta during human pregnancy ensures successful maintenance of placental development and fetal growth by stimulating trophoblast proliferation and the differentiation of cytotrophoblasts into syncytiotrophoblasts. Decreased levels of E2 are closely associated with obstetrical diseases such as preeclampsia (PE) in the clinic. However, the mechanisms underlying the inhibition of placental E2 biosynthesis remain poorly understood. Here, we report that regulator of G-protein signaling 2 (RGS2) affects E2 levels by regulating aromatase, a rate-limiting enzyme for E2 biosynthesis, by using human trophoblast-derived JEG-3 cells and human placental villus tissues. RGS2 enhanced the protein degradation of the transcription factor heart and neural crest derivatives expressed 1 (HAND1) by suppressing ubiquitin-specific protease 14 (USP14)-mediated deubiquitination of HAND1, resulting in the restoration of HAND1-induced trans-inactivation of the aromatase gene and subsequent increases in E2 levels. However, aromatase bound to RGS2 and repressed RGS2 GTPase activating protein (GAP) activity. Moreover, we observed a positive correlation between RGS2 and aromatase expression in clinical normal and preeclamptic placental tissues. Our results uncover a hitherto uncharacterized role of the RGS2-aromatase axis in the regulation of E2 production by human placental trophoblasts, which may pinpoint the molecular pathogenesis and highlight potential biomarkers for related obstetrical diseases.

PUS1 is a novel biomarker for evaluating malignancy of human renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most common malignancies. Despite the rapid development of the oncology research and surgical treatment, the prognosis of RCC has not significantly improved. Thus, exploration of the pathological molecular mechanism and development of new therapeutic targets of RCC are of great importance. Herein, by bioinformatic analysis and in vitro cell experiments, we report that, the expression of pseudouridine synthase 1 (PUS1), belonging to the family of PUS enzymes that participate in RNA modifications, is closely associated with RCC progression. In addition, the upregulated PUS1 expression results in the elevated RCC cancer cell viability, migration, invasion and colony formation ability, whereas the decreased PUS1 expression exerts the opposite effects on RCC cells. Thus, our findings show the potential role of PUS1 in RCC cells, providing with evidence that PUS1 is involved in RCC progression, which may help contribute to RCC diagnosis and intervention in clinic.

Cholesterol and Hedgehog Signaling: Mutual Regulation and Beyond.

The Hedgehog (HH) signaling is one of the key agents that govern the precisely regulated developmental processes of multicellular organisms in vertebrates and invertebrates. The HH pathway in the receiving cell includes Patched1, a twelve-pass transmembrane receptor, and Smoothened, a seven-transmembrane G-protein coupled receptor (GPCR), and the downstream GLI family of three transcriptional factors (GLI1-GLI3). Mutations of HH gene and the main components in HH signaling are also associated with numerous types of diseases. Before secretion, the HH protein undergoes post-translational cholesterol modification to gain full activity, and cholesterol is believed to be essential for proper HH signaling transduction. In addition, results from recent studies show the reciprocal effect that HH signaling functions in cholesterol metabolism as well as in cholesterol homeostasis, which provides feedback to HH pathway. Here, we hope to provide new insights into HH signaling function by discussing the role of cholesterol in HH protein maturation, secretion and HH signaling transduction, and the potential role of HH in regulation of cholesterol as well.

Role of ARID1A in the Regulation of Human Trophoblast Migration and Invasion.

Migration and invasion of trophoblasts is critical for human placental development, trophoblastic differentiation, and pregnancy-associated diseases. AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the SWI-SNF complex, has been suggested to participate in the regulation of fertility via placental disruption in mice. However, whether ARID1A regulates human placental development and function remains unknown. Here, using human trophoblast-like JEG-3 cell line, we report that ARID1A controls trophoblast cell migration and invasion. Overexpression of ARID1A inhibits JEG-3 cell migration and invasion, whereas knockdown of ARID1A promotes migration and invasion in JEG-3 cells. Mechanistically, while ARID1A reduces JEG-3 cell migration by down-regulation of Snail transcription, it restrains JEG-3 cell invasion by binding to and destabilization of MMP-9 protein. Finally, ARID1A is apparently up-regulated in placental tissues of preeclampsia compared to that of normal pregnancies. Our results thereby imply that ARID1A acts as a critical gene in supporting the physiological function of human mature placenta.

Tianma Gouteng Decoction Exerts Pregnancy-Protective Effects Against Preeclampsia via Regulation of Oxidative Stress and NO Signaling.

Preeclampsia (PE), a pregnancy-specific syndrome with the major molecular determinants of placenta-borne oxidative stress and consequently impaired nitric oxide (NO) generation, has been considered to be one of the leading causes of maternal morbidity as well as mortality and preterm delivery worldwide. Several medical conditions have been found to be associated with increased PE risk, however, the treatment of PE remains unclear. Here, we report that Tianma Gouteng Decoction (TGD), which is used clinically for hypertension treatment, regulates oxidative stress and NO production in human extravillous trophoblast-derived TEV-1 cells. In human preeclamptic placental explants, reactive oxygen species (ROS) levels were elevated and NO production was inhibited, while TGD treatment at different periods effectively down-regulated the H2O2-induced ROS levels and significantly up-regulated the H2O2-suppressed NO production in human TEV-1 cells. Mechanistically, TGD enhanced the activity of total nitric oxide synthase (TNOS), which catalyze L-arginine oxidation into NO, and simultaneously, TGD promoted the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), two isoforms of nitric oxide synthetases (NOS) in human placenta, resulting in the increased NO generation. More importantly, TGD administration not only increased the weight gain during pregnancy and revealed a hypotensive effect, but also improved the placental weight gain and attenuated fetal growth restriction in an NG-nitro-L-arginine methyl ester (L-NAME)-induced mouse PE-like model. Our results thereby provide new insights into the role of TGD as a potentially novel treatment for PE.

Regulator of G protein signaling 2 is inhibited by hypoxia-inducible factor-1α/E1A binding protein P300 complex upon hypoxia in human preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-related complication that causes maternal and fetal mortality. Despite extensive studies showing the role of hypoxia in preeclampsia progression, the specific mechanism remains unclear. The purpose of this study was to explore the possible mechanism underlying hypoxia in preeclampsia. METHODS: Human trophoblast-like JEG-3 cell line was used to investigate the molecular mechanisms underlying hypoxia contribution to preeclampsia and the expression correlation of key molecules was examined in human placental tissues. Methods include JEG-3 cell culture and hypoxia induction, RNA isolation and quantitative real-time PCR, transient transfection and dual-luciferase assay, western blot, immunoprecipitation, immunofluorescence staining, cell proliferation assay, chromatin immunoprecipitation assay, obtainment of human placental tissue sample and immunohistochemistry staining. RESULTS: Hypoxia-Inducible Factor-1α is up-regulated in clinical preeclampsia samples, where Regulator of G Protein Signaling 2 is down-regulated. Mechanistically, Hypoxia-Inducible Factor-1α is induced in response to hypoxia, which up-regulates E1A binding protein P300 expression and thereby forms a Hypoxia-Inducible Factor-1α/E1A binding protein P300 protein-protein complex that binds to the promoter of gene Regulator of G Protein Signaling 2 and subsequently inhibits the transcription of Regulator of G Protein Signaling 2, possibly contributing to the preeclampsia development. In addition, the expression of E1A binding protein P300 is increased in preeclampsia samples, and the expression of Regulator of G Protein Signaling 2 in preeclamptic placentas inversely correlates with the levels of E1A binding protein P300. CONCLUSION: Our findings may provide novel insights into understanding the molecular pathogenesis of preeclampsia and may be a prognostic biomarker and therapeutic target for preeclampsia.

Human HAND1 inhibits the conversion of cholesterol to steroids in trophoblasts.

Steroidogenesis from cholesterol in placental trophoblasts is fundamentally involved in the establishment and maintenance of pregnancy. The transcription factor gene heart and neural crest derivatives expressed 1 (Hand1) promotes differentiation of mouse trophoblast giant cells. However, the role of HAND1 in human trophoblasts remains unknown. Here, we report that HAND1 inhibits human trophoblastic progesterone (P4) and estradiol (E2) from cholesterol through downregulation of the expression of steroidogenic enzymes, including aromatase, P450 cholesterol side-chain cleavage enzyme (P450scc), and 3ß-hydroxysteroid dehydrogenase type 1 (3ß-HSD1). Mechanically, although HAND1 inhibits transcription of aromatase by directly binding to aromatase gene promoter, it restrains transcription of P450scc by upregulation of the methylation status of P450scc gene promoter through its binding to ALKBH1, a demethylase. Unlike aromatase and P450scc, HAND1 decreases 3ß-HSD1 mRNA levels by the reduction of its RNA stability through binding to and subsequent destabilizing protein HuR. Finally, HAND1 suppresses circulating P4 and E2 levels derived from JEG-3 xenograft and attenuates uterine response to P4 and E2. Thus, our results uncover a hitherto uncharacterized role of HAND1 in the regulation of cholesterol metabolism in human trophoblasts, which may help pinpoint the underlying mechanisms involved in supporting the development and physiological function of the human placenta.

Hedgehog signaling is controlled by Rac1 activity.

Rationale: The nuclear translocation of transcriptional factor Gli is indispensable for Hedgehog (Hh) signaling activation, whose deregulation causes cancer progressions; however, the mechanisms governing Gli nuclear translocation are poorly understood. Here, we report that the Gli translocation in response to Hh requires Rac1 activation. Methods: C3H10T1/2 cell line and mouse embryonic fibroblasts were used to explore the molecular mechanisms underlying Rac1 activity in regulation of Hh signaling transduction. Transgenic mouse strains and human medulloblastoma (MB) tissue samples were utilized to examine the role of Rac1 in Hh-directed limb bud development and MB progression. Results: We show that upon the binding of Hh to receptor Patched1 (Ptch1), receptor Smoothened (Smo) dissociates from Ptch1 and binds to Vav2, resulting in the increased phosphorylation levels of Vav2 at Y172, which further activates Rac1. The role of Rac1 is dependent on the regulation of phosphorylation levels of KIF3A at S689 and T694, which in turn affects IFT88 stability and subsequently dampens SuFu-Gli complex formation, leading to the release of Gli from the complex and the consequent translocation of Gli into the nucleus. Moreover, Vav2 phospho-Y172 levels are up-regulated in GFAP-Cre;SmoM2+/- mouse cerebellum and human Shh type MB tissues, whereas deficiency of Rac1 in mouse embryonic limb bud ectoderm (Prx1-Cre;Rac1f/f ) impedes Hh activation by disruption of Gli nuclear translocation. Conclusion: Together, our results uncover the Rac1 activation and the subsequent Gli translocation as a hitherto uncharacterized mechanism controlling Hh signaling and may provide targets for therapeutic intervention of this signaling pathway.

The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

Genes encoding subunits of SWItch/Sucrose Non-Fermenting (SWI/SNF) chromatin remodeling complexes are collectively mutated in 20% of all human cancers, among which the AT-rich interacting domain-containing protein 1A (ARID1A, also known as BAF250a, B120, C1orf4, Osa1) that encodes protein ARID1A is the most frequently mutated, and mutations in ARID1A have been found in various types of cancer. ARID1A is thought to play a significant role both in tumor initiation and in tumor suppression, which is highly dependent upon context. Recent molecular mechanistic research has revealed that ARID1A participates in tumor progression through its effects on control of cell cycle, modulation of cellular functions such as EMT, and regulation of various signaling pathways. In this review, we synthesize a mechanistic understanding of the role of ARID1A in human tumor initiation as well as in tumor suppression and further discuss the implications of these new discoveries for potential cancer intervention. We also highlight the mechanisms by which mutations affecting the subunits in SWI/SNF complexes promote cancer.