Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

Xu, Jiawei; Wang, Yulei; Hua, Xiaohui; Xu, Jiheng; Tian, Zhongxian; Jin, Honglei; Li, Jingxia; Wu, Xue-Ru; Huang, Chuanshu

doi:10.18632/oncotarget.8746

Cited by 18 publications

(18 citation statements)

References 50 publications

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“…As an identified tumor suppressive gene, multiple lines of evidence reveal the role of PHLPP2 in tumor progression . PHLPP2 is involved in the inhibition of malignant behaviors of cancer attributed to the suppression of prosurvival signaling such as through the PI3K/Akt signaling pathway .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, PHLPP2 can dephosphorylate and stabilize the Myc oncogene to suppress the progression of prostate cancer . A recent study reported on a novel molecular cascade of PHLPP2/CREB/miR‐302d that mediates cell cycle progression and anchorage‐independent growth . Therefore, the identification of PHLPP2 as an effective prognostic biomarker is reasonable.…”

Section: Discussionmentioning

confidence: 99%

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PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

Wang

Tian

et al. 2019

Thoracic Cancer

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Background PH domain and leucine‐rich repeat protein phosphatase 2 (PHLPP2) has been reported to be a potent tumor suppressor in many human cancers. However, PHLPP2 has not been fully researched as a putative clinical prognostic biomarker of lung cancer. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases including data on 1383 non‐small cell lung cancer (NSCLC) patients were used to determine PHLPP2 expression. PHLPP2 expression was then examined by immunohistochemistry, and its clinical significance analyzed in 134 NSCLC patients, including 73 patients with adenocarcinoma and 81 with squamous cell carcinoma. Results We found PHLPP2 expression to be less pronounced in NSCLC tissue samples than that in nontumoral lung tissues according to data taken from TCGA and GEO datasets; this outcome was further validated by immunohistochemistry assay. The low PHLPP2 expression level was found to be associated with the presence of lymph node metastasis (P = 0.003). Importantly, PHLPP2 was found to be an independent indicator of prognosis for overall (hazard ratio [HR] = 0.520, 95% confidence interval [Cl] = 0.327–0.827; P = 0.006) and disease‐free survival (HR = 0.489, 95% Cl = 0.308–0.775; P = 0.002) in patients with surgically‐resected NSCLC by multivariate analysis. Conclusion Taken together, our findings show that PHLPP2 is a robust clinical marker for NSCLC survival and could serve as a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

Wang

Tian

et al. 2019

Thoracic Cancer

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“…4d). As a precursor of p52, p100 could function in p52-independent fashion [37]. Thus, we next evaluated the potential contribution of p100 to EGFR expression by ectopic expressing p100 in T24T cells.…”

Section: Resultsmentioning

confidence: 99%

“…The miR-200a knockdown plasmid was purchased from GeneCopoeia (Rockville, MD, USA). The overexpression of HA-∆RING plasmid, the TAM67 plasmid, a well-characterized dominant-negative c-Jun mutant, and the p100 overexpression plasmid were described in our previously studies [19, 36, 37]. Wild-type EGFR 3′-UTR luciferase reporter is a kind gift from Professor Benjamin Purow (University of Virginia Health System, VA) [38].…”

Section: Methodsmentioning

confidence: 99%

XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell

et al. 2017

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BackgroundThe X-linked inhibitor of apoptosis protein (XIAP) is a well-known potent apoptosis suppressor and also participates in cancer cell biological behaviors, therefore attracting great attentions as a potential antineoplastic therapeutic target for past years. Anti-IAP therapy is reported to be closely related to epidermal growth factor receptor (EGFR) expression level. However, whether and how XIAP modulates EGFR expression remains largely unknown.MethodsHuman XIAP was knockdown with short-hairpin RNA in two different bladder cancer cell lines, T24T and UMUC3. Two XIAP mutants, XIAP ∆BIR (deletion of N-terminal three BIR domains) and XIAP ∆RING (deletion of C-terminal RING domain and keeping the function of BIR domains), were generated to determine which domain is involved in regulating EGFR.ResultsWe found here that lacking of XIAP expression resulted in a remarkable suppression of EGFR expression, consequently leading to the deficiency of anchorage-independent cell growth. Further study demonstrated that BIR domain of XIAP was crucial for regulating the EGFR translation by suppressing the transcription and expression of miR-200a. Mechanistic studies indicated that BIR domain activated the protein phosphatase 2 (PP2A) activity by decreasing the phosphorylation of PP2A at Tyr307 in its catalytic subunit, PP2A-C. Such activated PP2A prevented the deviant phosphorylation and activation of MAPK kinases/MAPKs, their downstream effector c-Jun, and in turn inhibiting transcription of c-Jun-regulated the miR-200a.ConclusionsOur study uncovered a novel function of BIR domain of XIAP in regulating the EGFR translation, providing significant insight into the understanding of the XIAP overexpression in the cancer development and progression, further offering a new theoretical support for using XIAP BIR domain and EGFR as targets for cancer therapy.

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“…14 and tumor suppressor genes. 15 Although our most recently studies demonstrate that p100 but not p52, inhibits BC growth by targeting Cyclin D1 protein translation through PHLPP2/CREB/miR-302d axis, 16 the potential participation and molecular mechanisms underlying p52 regulation of BC cell invasion have not been characterized.…”

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confidence: 97%

NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR‐145/Sp1/USP8‐dependent axis

Hua

Jin

et al. 2019

Molecular Carcinogenesis

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Although overexpression of the non‐canonical NFκB subunit p52 has been observed in several tumors, the function and mechanism of p52 in bladder cancer (BC) are less well understood. Here, we aimed at understanding the role and mechanism underlying p52 regulation of BC invasion. Human p52 was stably knockdown with shRNA targeting p52 in two bladder cancer cell lines (T24 and UMUC3). Two constitutively expressing constructs, p52 and p100, were stably transfected in to T24 or UMUC3, respectively. The stable transfectants were used to determine function and mechanisms responsible for p52 regulation of BC invasion. We demonstrate that p52 mediates human BC invasion. Knockdown of p52 impaired bladder cancer invasion by reduction of rhogdiβ mRNA stability and expression. Positively regulation of rhogdiβ mRNA stability was mediated by p52 promoting AUF1 protein degradation, consequently resulting in reduction of AUF1 binding to rhogdiβ mRNA. Further studies indicated that AUF1 protein degradation was mediated by upregulating USP8 transcription, which was modulated by its negative regulatory transcription factor Sp1. Moreover, we found that p52 upregulated miR‐145, which directly bound to the 3′‐UTR of sp1 mRNA, leading to downregulation of Sp1 protein translation. Our results reveal a comprehensive pathway that p52 acts as a positive regulator of BC invasion by initiating a novel miR‐145/Sp1/USP8/AUF1/RhoGDIβ axis. These findings provide insight into the understanding of p52 in the pathology of human BC invasion and progression, which may be useful information in the development of preventive and therapeutic approaches for using p52 as a potential target.

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Inhibition of PHLPP2/cyclin D1 protein translation contributes to the tumor suppressive effect of NFκB2 (p100)

Cited by 18 publications

References 50 publications

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

PHLPP2 as a novel metastatic and prognostic biomarker in non‐small cell lung cancer patients

XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell

NFκB2 p52 stabilizes rhogdiβ mRNA by inhibiting AUF1 protein degradation via a miR‐145/Sp1/USP8‐dependent axis

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