ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC

Griffin, Nicolas I; Sharma, Geeta; Zhao, Xiangshan; Mirza, Sameer; Srivastava, Shashank; Davé, Bhavana J.; Aleskandarany, Mohammed A.; Rakha, Emad A.; Mohibi, Shakur; Band, Hamid

doi:10.1186/s13058-016-0770-9

Cited by 12 publications

(9 citation statements)

References 43 publications

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“…In our study, c-Myc inhibited miR-567 expression by binding to its promoter region, thus formed a miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop, by which miR-567 suppressed GC tumourigenesis and drug resistance. c-Myc is an oncogenic transcription factor playing a pivotal role in the control of cell proliferation, apoptosis and drug resistance [[36], [37], [38]]. Mutated c-Myc is observed in many cancers and resulted in persistent expression of c-Myc protein, which causes abnormal expression of many genes.…”

Section: Discussionmentioning

confidence: 99%

A miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop regulates tumour growth and chemoresistance in gastric cancer

Zhang

Yao

et al. 2019

eBioMedicine

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Background Gastric cancer (GC) ranks the fifth most common cancer, and chemotherapy is one of the most common treatments for GC. However, chemoresistance limits the effectiveness of chemotherapy and leads to treatment failure. This study aims to investigate the biological effect of miR-567 on gastric tumourigenesis and chemoresistance and reveal the possible mechanism. Methods We measured the expression of miR-567 in 37 paired normal and stomach tumour specimens, as well as GC cell lines by Real-time PCR. The functional effects of miR-567 were validated using in vitro and in vivo assays. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were conducted for target evaluation, western blot assay was used to confirm the relationships. Findings Our data showed that miR-567 was downregulated in gastric tissues and gastric cancer cells compared with normal tissues and gastric epithelial cells. In vitro , Gain- and lose-of-function assays showed miR-567 not only weakened cells proliferative ability, but also sensitized GC cells to 5-FU and oxaliplatin. In vivo , miR-567 overexpression significantly repressed the tumourigenesis of GC cells compared with the vector control. Mechanistic analysis showed that PIK3AP1 activated AKT phosphorylation in GC. Meanwhile, miR-567 directly targeted PIK3AP1 to inactivate PI3K/AKT/c-Myc pathway and c-Myc inversely regulated miR-567 expression, thus forming a miR-567-PIK3AP1- PI3K/AKT-c-Myc feedback loop explaining the function of miR-567. Interpretation Our studies revealed that miR-567 acts as a tumour suppressor gene and suppresses GC tumorigenesis and chemoresistance via a miR-567-PIK3AP1- PI3K/AKT-c-Myc feedback loop. These results suggest that miR-567 may serve as a target for chemoresistance and a potential prognostic biomarker for GC.

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Section: Discussionmentioning

confidence: 99%

A miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop regulates tumour growth and chemoresistance in gastric cancer

Zhang

Yao

et al. 2019

eBioMedicine

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“…p27 is a major regulator of proliferation which exhibits inhibitory activity by binding cyclin E/Cdk2 complexes [24]. While, as an oncogene, c-myc abrogates p27 function in proliferation [25]. MMPs are a family of enzymes that degrade extracellular matrix (ECM), which promote tumor growth and metastasis [26].…”

Section: Resultsmentioning

confidence: 99%

The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR)

Xiong

Wang

et al. 2017

Cell Physiol Biochem

101

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Backgrounds/Aims: Long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) is involved in the progression of several tumors. The interaction between lncRNA and miRNA or miRNA’s target genes is reported to play crucial roles in malignancy. In addition, Androgen receptor (AR) is considered to be involved in bladder cancer progression. In this study, we investigated the role of XIST in human bladder cancer and its interaction with miR-124 and AR. Methods: XIST and AR expression was detected in bladder tumor samples and cell lines. Effects of XIST and AR on bladder cancer cells growth, invasion and migration were analyzed. Bioinformatic analysis and luciferase assays were used to identify the interaction among XIST, AR and miR-124. The correlations of miR-124 with XIST and AR in bladder cancer samples were statistically analyzed. Results: XIST and AR were upregulated in bladder cancer tissues and positively correlated. Higher XIST and AR expression were related to poorer TNM stage of bladder cancer. XIST knockdown reduced bladder cancer cells’ proliferation, invasion and migration. While this inhibitory effect could be partially restored by AR overexpression. XIST inhibited miR-124 expression by directly targeting. Moreover, miR-124 could bind to the 3’UTR of AR to regulate its expression. MiR-124 inhibition partially restored the XIST knockdown-induced reduction of AR, c-myc, p27, MMP13 and MMP9 expression. In bladder cancer tissues, miR-124 level was inversely correlated with the expression of XIST and AR, respectively. Conclusion: These findings indicated that XIST might be an oncogenic lncRNA that promoted the bladder cancer growth, invasion and migration via miR-124 dependent AR regulation.

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“… 2,4,5,34 We have shown that ADA3 protein is mislocalized from nucleus to cytoplasm, and is overexpressed in breast cancer patients, in particular those with EGFR/HER2 overexpression, and the mislocalization/overexpression of ADA3 correlates with poor prognosis and short survival of patients. 3,27 To begin to explore the mechanistic links between ADA3 and cell proliferation, we recently demonstrated that ADA3 is post-translationally modified by acetylation, and that acetylation is critical for the role of ADA3 to promote cell cycle progression. 7 In this study, we reveal new mechanistic links that control ADA3 acetylation during cell cycle progression downstream of prototype receptor tyrosine kinases of the EGFR family.…”

Section: Discussionmentioning

confidence: 99%

“…76N-TERT, immortalized human mammary epithelial cell line was grown in DFCI-1 medium and where necessary, was growth factor deprived in DFCI-3 medium, as described earlier. 3,13 HEK-293T and A549, and UACC812 and MDA-MB-468, and SKBR-3 were cultured in DMEM, α-MEM and RPMI 1640, respectively. All media were supplemented with 10% fetal bovine serum (FBS), 10 μg/ml gentamycin, 1 mM sodium pyruvate, 10 mM HEPES, 2 mM L -glutamine, 1x minimal non-essential amino acids.…”

Section: Methodsmentioning

confidence: 99%

Epidermal Growth Factor Receptor activation promotes ADA3 acetylation through the AKT-p300 pathway

et al. 2017

Self Cite

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The ADA3 (Alteration/Deficiency in Activation 3) protein is an essential adaptor component of several Lysine Acetyltransferase (KAT) complexes involved in chromatin modifications. Previously, we and others have demonstrated a crucial role of ADA3 in cell cycle progression and in maintenance of genomic stability. Recently, we have shown that acetylation of ADA3 is key to its role in cell cycle progression. Here, we demonstrate that AKT activation downstream of Epidermal Growth Factor Receptor (EGFR) family proteins stimulation leads to phosphorylation of p300, which in turn promotes the acetylation of ADA3. Inhibition of upstream receptor tyrosine kinases (RTKs), HER1 (EGFR)/HER2 by lapatinib and the accompanying reduction of phospho-AKT levels led to a decrease in p300 phosphorylation and ADA3 protein levels. The p300/PCAF inhibitor garcinol also destabilized the ADA3 protein in a proteasome-dependent manner and an ADA3 mutant with K→R mutations exhibited a marked increase in half-life, consistent with opposite role of acetylation and ubiquitination of ADA3 on shared lysine residues. ADA3 knockdown led to cell cycle inhibitory effects, as well as apoptosis similar to those induced by lapatinib treatment of HER2+ breast cancer cells, as seen by accumulation of CDK inhibitor p27, reduction in mitotic marker pH3(S10), and a decrease in the S-phase marker PCNA, as well as the appearance of cleaved PARP. Taken together our results reveal a novel RTK-AKT-p300-ADA3 signaling pathway involved in growth factor-induced cell cycle progression.

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ADA3 regulates normal and tumor mammary epithelial cell proliferation through c-MYC

Cited by 12 publications

References 43 publications

A miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop regulates tumour growth and chemoresistance in gastric cancer

A miR-567-PIK3AP1-PI3K/AKT-c-Myc feedback loop regulates tumour growth and chemoresistance in gastric cancer

The Long Non-Coding RNA XIST Interacted with MiR-124 to Modulate Bladder Cancer Growth, Invasion and Migration by Targeting Androgen Receptor (AR)

Epidermal Growth Factor Receptor activation promotes ADA3 acetylation through the AKT-p300 pathway

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