Browse
Submit Data
Databases
API
Help

Dataset Information

29 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

P53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth

ABSTRACT: Cholesterol is essential for membrane biogenesis, cell proliferation and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions，p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis，in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD) -induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.

SUBMITTER: Dr. Huishan Sun

PROVIDER: S-SCDT-EMBOR-2021-52537V1 | biostudies-other |

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth.

Project description:Cholesterol is essential for membrane biogenesis, cell proliferation, and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions, p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis, in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD)-induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.

| S-EPMC8490977 | biostudies-literature

p53 transcriptionally regulates SQLE to modulate cholesterol synthesis and tumor growth

Project description:Cholesterol is essential for membrane biogenesis, cell proliferation and differentiation. The role of cholesterol in cancer development and the regulation of cholesterol synthesis are still under active investigation. Here we show that under normal-sterol conditions，p53 directly represses the expression of SQLE, a rate-limiting and the first oxygenation enzyme in cholesterol synthesis，in a SREBP2-independent manner. Through transcriptional downregulation of SQLE, p53 represses cholesterol production in vivo and in vitro, leading to tumor growth suppression. Inhibition of SQLE using small interfering RNA (siRNA) or terbinafine (a SQLE inhibitor) reverses the increased cell proliferation caused by p53 deficiency. Conversely, SQLE overexpression or cholesterol addition promotes cell proliferation, particularly in p53 wild-type cells. More importantly, pharmacological inhibition or shRNA-mediated silencing of SQLE restricts nonalcoholic fatty liver disease (NAFLD) -induced liver tumorigenesis in p53 knockout mice. Therefore, our findings reveal a role for p53 in regulating SQLE and cholesterol biosynthesis, and further demonstrate that downregulation of SQLE is critical for p53-mediated tumor suppression.

2021-07-18 | GSE176112 | GEO

p53 transcriptionally regulates SQLE to modulate cholesterol synthesis and tumor growth

Project description:p53 transcriptionally regulates SQLE to modulate cholesterol synthesis and tumor growth

| PRJNA734935 | ENA

The tumor suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse.

Project description:The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts Semaphorin 3A (Sema3A)-induced growth cone collapse. Within the nervous system, however, the transcriptional regulation of cGKI is still obscure. Recently, the transcription factor and tumor suppressor p53 has been reported to promote neurite outgrowth by regulating the gene expression of factors that promote growth cone extension, but specific p53 targets genes that may counteract growth cone collapse have not been identified so far. Here, we show that p53 promotes cGKI expression in neuronal-like PC-12 cells and primary neurons by occupying specific regulatory elements in a chromatin environment during neuronal maturation. Importantly, we demonstrate that p53-dependent expression of cGKI is required for the ability of cGMP to counteract growth cone collapse. Growth cone retraction mediated by Sema3A is overcome by cGMP only in wild-type, but not in p53-null dorsal root ganglia. Reconstitution of p53 levels is sufficient to recover both cGKI expression and the ability of cGMP to counteract growth cone collapse, while cGKI overexpression rescues growth cone collapse in p53-null primary neurons. In conclusion, this study identifies p53 as a transcription factor that regulates the expression of cGKI during neuronal maturation and cGMP-dependent inhibition of growth cone collapse.

| S-EPMC2822954 | biostudies-literature

Statins significantly repress rotavirus replication through downregulation of cholesterol synthesis.

Project description:Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.

| S-EPMC8354672 | biostudies-literature

DeltaNp63 transcriptionally regulates ATM to control p53 Serine-15 phosphorylation.

Project description:BackgroundDeltaNp63alpha is an epithelial progenitor cell marker that maintains epidermal stem cell self-renewal capacity. Previous studies revealed that UV-damage induced p53 phosphorylation is confined to DeltaNp63alpha-positive cells in the basal layer of human epithelium.ResultsWe now report that phosphorylation of the p53 tumour suppressor is positively regulated by DeltaNp63alpha in immortalised human keratinocytes. DeltaNp63alpha depletion by RNAi reduces steady-state ATM mRNA and protein levels, and attenuates p53 Serine-15 phosphorylation. Conversely, ectopic expression of DeltaNp63alpha in p63-null tumour cells stimulates ATM transcription and p53 Serine-15 phosphorylation. We show that ATM is a direct DeltaNp63alpha transcriptional target and that the DeltaNp63alpha response element localizes to the ATM promoter CCAAT sequence. Structure-function analysis revealed that the DeltaNp63-specific TA2 transactivation domain mediates ATM transcription in coordination with the DNA binding and SAM domains.ConclusionsGermline p63 point mutations are associated with a range of ectodermal developmental disorders, and targeted p63 deletion in the skin causes premature ageing. The DeltaNp63alpha-ATM-p53 damage-response pathway may therefore function in epithelial development, carcinogenesis and the ageing processes.

| S-EPMC3098010 | biostudies-literature

SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.

Project description:Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) from increased gene transcription activated by SOX4 de novo expressed in PDAC. Via chromatin-immunoprecipitation, luciferase promoter activity assay and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. We further demonstrate that SOX4 levels parallel with the summed expression of SEMA3/Plexin family members (P = 0.033, NPar Kruskal-Wallis one-way analysis), which also correlates with poor survival in human PDAC (P = 0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2 and miR-335, both of which target SOX4 for degradation, are co-repressed in human PDAC cases associated with up-regulated SOX4 in a statistically significant way. In conclusion, we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer.

| S-EPMC3520963 | biostudies-literature

Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53.

Project description:Akt regulates a diverse array of cellular functions, including cell survival, proliferation, differentiation, and metabolism. Although a number of molecules have been identified as upstream regulators and downstream targets of Akt, the mechanisms by which Akt regulates these cellular processes remain elusive. Here, we demonstrate that a novel transcription factor, PHF20/TZP (referring to Tudor and zinc finger domain containing protein), binds to Akt and induces p53 expression at the transcription level. Knockdown of PHF20 significantly reduces p53. PHF20 inhibits cell growth, DNA synthesis, and cell survival. Akt phosphorylates PHF20 at Ser(291) in vitro and in vivo, which results in its translocation from the nucleus to the cytoplasm and attenuation of PHF20 function. These data indicate that PHF20 is a substrate of Akt and plays a role in Akt cell survival/growth signaling.

| S-EPMC3322870 | biostudies-literature

14-3-3 sigma positively regulates p53 and suppresses tumor growth.

Project description:The 14-3-3 sigma (sigma) protein, a negative regulator of the cell cycle, is a human mammary epithelium-specific marker that is downregulated in transformed mammary carcinoma cells. It has also been identified as a p53-inducible gene product involved in cell cycle checkpoint control after DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, detailed mechanisms of how cell cycle regulation occurs remain unclear. Decreased expression of 14-3-3 sigma was recently reported in several types of carcinomas, further suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. However, this possible tumor-suppressive role of 14-3-3 sigma has not yet been characterized. Here, we studied the link between 14-3-3 sigma activities and p53 regulation. We found that 14-3-3 sigma interacted with p53 in response to the DNA-damaging agent adriamycin. Importantly, 14-3-3 sigma expression led to stabilized expression of p53. In studying the molecular mechanism of this increased stabilization of p53, we found that 14-3-3 sigma antagonized the biological functions of Mdm2 by blocking Mdm2-mediated p53 ubiquitination and nuclear export. In addition, we found that 14-3-3 sigma facilitated the oligomerization of p53 and enhanced p53's transcriptional activity. As a target gene of p53, 14-3-3 sigma appears to have a positive feedback effect on p53 activity. Significantly, we also showed that overexpression of 14-3-3 sigma inhibited oncogene-activated tumorigenicity in a tetracycline-regulated 14-3-3 sigma system. These results defined an important p53 regulatory loop and suggested that 14-3-3 sigma expression can be considered for therapeutic intervention in cancers.

| S-EPMC230310 | biostudies-other

A p53/lnc-Ip53 Negative Feedback Loop Regulates Tumor Growth and Chemoresistance.

Project description:Acetylation is a critical mechanism to modulate tumor-suppressive activity of p53, but the causative roles of long non-coding RNAs (lncRNAs) in p53 acetylation and their biological significance remain unexplored. Here, lncRNA LOC100294145 is discovered to be transactivated by p53 and is thus designated as lnc-Ip53 for lncRNA induced by p53. Furthermore, lnc-Ip53 impedes p53 acetylation by interacting with histone deacetylase 1 (HDAC1) and E1A binding protein p300 (p300) to prevent HDAC1 degradation and attenuate p300 activity, resulting in abrogation of p53 activity and subsequent cell proliferation and apoptosis resistance. Mouse xenograft models reveal that lnc-Ip53 promotes tumor growth and chemoresistance in vivo, which is attenuated by an HDAC inhibitor. Silencing lnc-Ip53 inhibits the growth of xenografts with wild-type p53, but not those expressing acetylation-resistant p53. Consistently, lnc-Ip53 is upregulated in multiple cancer types, including hepatocellular carcinoma (HCC). High levels of lnc-Ip53 is associated with low levels of acetylated p53 in human HCC and mouse xenografts, and is also correlated with poor survival of HCC patients. These findings identify a novel p53/lnc-Ip53 negative feedback loop in cells and indicate that abnormal upregulation of lnc-Ip53 represents an important mechanism to inhibit p53 acetylation/activity and thereby promote tumor growth and chemoresistance, which may be exploited for anticancer therapy.

| S-EPMC7610266 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data