PTEN deficiency in TNBC provides vulnerability to co-targeting KDM4B and PI3K through over-activation of Unfolded Protein Response pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE103018 | GEO | 2018/08/27
REPOSITORIES: GEO
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Project description:PTEN deficiency in breast cancer leads to resistance to PI3K-AKT inhibitor treatment despite aberrant activation of this signaling pathway. Here, we report that genetic depletion or small molecule inhibition of KDM4B histone demethylase activates the unfolded protein response (UPR) pathway and results in preferential apoptosis in PTEN-deficient triple-negative breast cancers (TNBCs). Intriguingly, this function of KDM4B on UPR requires its demethylase activity but is independent of its canonical role in histone modification, and acts through its cytoplasmic interaction with eIF2?, a crucial component of UPR signaling, resulting in reduced phosphorylation of this component. Targeting KDM4B in combination with PI3K inhibition induces further activation of UPR, leading to robust synergy in apoptosis. These findings identify KDM4B as a therapeutic vulnerability in PTEN-deficient TNBC that otherwise would be resistant to PI3K inhibition.
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Project description:To comprehensively analyze the PTEN-PI3K-AKT pathway in T-ALL, we examined diagnostic DNA samples from a series of children with T-ALL by array CGH and sequence analysis, and identified genetic lesions in PTEN, PI3K or AKT in 47.7 % (n = 21 of 44) of cases. Furthermore, we identified a striking clustering of PTEN mutations in exon 7 in primary T-ALL patient samples, all of which encode mutations predicted to truncate the C2 domain without disrupting the phosphatase domain of PTEN. Induction chemotherapy failed in three of the four patients whose lymphoblasts harbored PTEN deletions at the time of diagnosis, while no induction failures occurred in the 12 cases with PTEN exon 7 mutations (P = 0.007), suggesting that PTEN deletion has more adverse therapeutic consequences than mutational disruptions that preserve the phosphatase domain. These findings provide a firm rationale for the development of therapies targeting the PI3K-AKT pathway in T-ALL.
2009-12-01 | GSE14959 | GEO
Project description:The transcription factor Pax5 is known to control B-cell development, but its role in mature B- cells is largely enigmatic. Here, we demonstrate by conditional mutagenesis in peripheral B- lymphocytes that B-1a, marginal zone (MZ) and germinal center B-cells as well as plasma cells are not generated upon loss of Pax5. Follicular (FO) B-cells tolerate the loss of Pax5 but have a shortened half-life. The Pax5-deficient FO B-cells fail to proliferate upon B-cell receptor or Toll- like receptor stimulation due to impaired PI3K-AKT signaling, which is caused by increased expression of PTEN, a negative regulator of the PI3K pathway. Pax5 restrains PTEN protein expression at the posttranscriptional level, likely involving Pten-targeting microRNAs. Additional PTEN loss in Pten,Pax5 double-mutant mice rescues FO B-cell numbers and the development of MZ B-cells. Hence, the posttranscriptional downregulation of PTEN expression is a dominant function of Pax5 that facilitates the differentiation and survival of mature B cells, thereby promoting humoral immunity.
2021-06-14 | GSE103260 | GEO
Project description:PTEN loss, one of the most frequent mutations in prostate cancer (PC), is presumed to drive disease progression through AKT activation. However, two transgenic PC models with Akt activation plus Rb loss exhibited different metastatic development: Pten/RbPE:-/- mice produced systemic metastatic adenocarcinomas with high AKT2 activation, whereas RbPE:-/- mice deficient for the Src-scaffolding protein, Akap12, induced high-grade prostatic intraepithelial neoplasias and indolent lymph node dissemination, correlating with upregulated phosphotyrosyl PI3K-p85α. Using PC cells isogenic for PTEN, we show that PTEN-deficiency correlated with dependence on both p110β and AKT2 for in vitro and in vivo parameters of metastatic growth or motility, and with downregulation of SMAD4, a known PC metastasis suppressor. In contrast, PTEN expression, which dampened these oncogenic behaviors, correlated with greater dependence on p110α plus AKT1. Our data suggest that metastatic PC aggressiveness is controlled by specific PI3K/AKT isoform combinations influenced by divergent Src activation or PTEN-loss pathways.
2023-11-01 | GSE242387 | GEO
Project description:Phosphatase and tensin homologue (PTEN) is the most frequently mutated tumor suppressor gene in human prostate cancer. Synthetic essentiality is defined as cancer that harbors a specific tumor suppressor deficiency is dependent on synthetic-essential genes for the malignant phenotypes. Recently, targeting such synthetic-essential genes has become an attractive treatment approach for cancers that acquire loss-of-function mutations in tumor suppressor genes. Here, we show that AT-rich interaction domain 4B (ARID4B) functions as a synthetic-essential gene in prostate tumorigenesis driven by PTEN deficiency. This functional interaction between ARID4B and PTEN is recapitulated in the mouse model carrying prostate-specific deletions of Pten and Arid4b in which ablation of ARID4B attenuated prostate cancer progression elicited by loss of PTEN. Although the tumor suppressor function of PTEN is most attributed to its lipid phosphatase activity that counters the PI3K action in cytoplasm, we identified the PTEN-ARID4B-PI3K axis in which nuclear PTEN inhibits expression of ARID4B, while ARID4B serves as a transcriptional activator of the PI3K subunits PIK3CA and PIK3R2 to trigger the PI3K/AKT pathway. Our study further demonstrated that the reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, indicating a mechanism by which ARID4B activates these promoters. Finally, a three-gene signature consisting of PTEN, ARID4B, and PI3K substantially improves the predictive power for tumor recurrence in human prostate cancer patients, underscoring the clinical significance of this newly identified PTEN-ARID4B-PI3K axis. These findings reveal a novel synthetic-essential relationship between ARID4B and PTEN, thus exposing a previously unidentified cancer-specific vulnerability, and supporting ARID4B as a potential therapeutic target for prostate cancer patients with PTEN mutations.
2019-08-23 | GSE116668 | GEO
Project description:Phosphatase and tensin homologue (PTEN) is the most frequently mutated tumor suppressor gene in human prostate cancer. Synthetic essentiality is defined as cancer that harbors a specific tumor suppressor deficiency is dependent on synthetic-essential genes for the malignant phenotypes. Recently, targeting such synthetic-essential genes has become an attractive treatment approach for cancers that acquire loss-of-function mutations in tumor suppressor genes. Here, we show that AT-rich interaction domain 4B (ARID4B) functions as a synthetic-essential gene in prostate tumorigenesis driven by PTEN deficiency. This functional interaction between ARID4B and PTEN is recapitulated in the mouse model carrying prostate-specific deletions of Pten and Arid4b in which ablation of ARID4B attenuated prostate cancer progression elicited by loss of PTEN. Although the tumor suppressor function of PTEN is most attributed to its lipid phosphatase activity that counters the PI3K action in cytoplasm, we identified the PTEN-ARID4B-PI3K axis in which nuclear PTEN inhibits expression of ARID4B, while ARID4B serves as a transcriptional activator of the PI3K subunits PIK3CA and PIK3R2 to trigger the PI3K/AKT pathway. Our study further demonstrated that the reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, indicating a mechanism by which ARID4B activates these promoters. Finally, a three-gene signature consisting of PTEN, ARID4B, and PI3K substantially improves the predictive power for tumor recurrence in human prostate cancer patients, underscoring the clinical significance of this newly identified PTEN-ARID4B-PI3K axis. These findings reveal a novel synthetic-essential relationship between ARID4B and PTEN, thus exposing a previously unidentified cancer-specific vulnerability, and supporting ARID4B as a potential therapeutic target for prostate cancer patients with PTEN mutations.
2019-08-23 | GSE116669 | GEO
Project description:The expression levels of JMJD6 and its correlation with H2A.XY39ph differed in TNBC and non-TNBC cells. In addition, we have previously shown that H2A.XY39ph levels are positively correlated with tumor size, histological grade and advanced TNM stage in breast cancer. To analyze the role of JMJD6 in regulating the characteristics of different subtypes of breast cancer, the transcriptomes of TNBC cells (SUM159) and non-TNBC cells (HCC1569) that overexpressed JMJD6 were compared. We speculate that JMJD6 overexpression cause autophagy pathway activation in TNBC via enhancing ATG genes expression.
2023-10-01 | E-MTAB-6517 | biostudies-arrayexpress
Project description:Triple-negative breast cancer [TNBC, lacks expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2/Neu] remains one of the most aggressive subtypes, affects the youngest patients, and still lacks an effective targeted therapy. Both phosphatidylinositol-3-kinase (PI3K)-α and -β contribute to oncogenesis of solid tumors, including the development of breast cancer. Inositol polyphosphate-4-phosphatase type II (INPP4B) catalyzes the removal of the 4'-phosphate of phosphatidylinositol-(3, 4)-bisphosphate (PI-3,4-P2), creating phosphatidylinositol-3-phosphate. There is debate concerning whether PI-3,4-P2 contributes to Akt and downstream effector activation with the known canonical signaling second messenger, phosphatidylinositol-(3, 4, 5)-trisphosphate (PIP3). If PI-3,4-P2 is a positive effector, INPP4B would be a negative regulator of PI3K signaling, and there is some evidence to support this. Utilizing phosphatase and tensin homolog deleted on chromosome ten (PTEN)-null triple-negative breast tumor cell lines, it was unexpectedly found that silencing INPP4B decreased basal phospho-Akt (pAkt) and cellular proliferation, and in most cases sensitized cells to PI3K-α and PI3K-β isoform-specific inhibitors. Conversely, overexpression of INPP4B desensitized cells to PI3K inhibitors in a phosphatase activity-dependent manner. In summary, the current investigation of INPP4B in PTEN-null TNBC suggests new mechanistic insight and the potential for targeted therapy for this aggressive subset of breast cancer.Implications: These data support a model where PI-3,4-P2 is inhibitory toward PI3K, revealing a novel feedback mechanism under conditions of excessive signaling, and potentially an indication for PI3K-β isoform-specific inhibitors in PTEN-null TNBC that have lost INPP4B expression. Mol Cancer Res; 15(6); 765-75. ©2017 AACR.
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Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
2016-12-01 | E-MTAB-5286 | biostudies-arrayexpress
Project description:We found that GSCs were highly sensitive to proteasome inhibition due to an underlying dependency on an increased protein synthesis rate, and loss of autophagy, associated with PTEN loss and activation of the PI3K/mTOR pathway. In contrast, combinatory inhibition of autophagy and the proteasome, resulted in enhanced cytotoxicity specifically in GSCs that did express PTEN. Finally, proteasome inhibition specifically increased cell death markers in 3D glioblastoma organoids, suppressed tumor growth, and increased survival of mice orthotopically engrafted with GSCs. As perturbations of the PI3K/mTOR pathway occur in nearly 50% of GBMs, these findings suggest that a significant fraction of these tumors could be vulnerable to proteasome inhibition.
2020-12-29 | GSE163906 | GEO