The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

Nowak, Dawid G.; Katsenelson, Ksenya Cohen; Watrud, Kaitlin; Chen, Muhan; Mathew, Grinu; D'Andrea, Vincent; Lee, Matthew F.; Swamynathan, Manojit Mosur; Casanova-Salas, Irene; Jibilian, Megan C.; Buckholtz, Caroline L.; Ambrico, Alexandra; Pan, Chun‐Hao; Wilkinson, John E.; Newton, Alexandra C.; Trotman, Lloyd C.

doi:10.1083/jcb.201902048

Cited by 39 publications

(25 citation statements)

References 62 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%

“…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 . 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 .…”

Section: Discussionmentioning

confidence: 99%

“…As an identified tumor suppressive gene, multiple lines of evidence reveal the role of PHLPP2 in tumor progression. [7][8][9]13,23,29,[41][42][43] 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. 13,29 In addition, PHLPP2 can dephosphorylate and stabilize the Myc oncogene to suppress the progression of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…13,29 In addition, PHLPP2 can dephosphorylate and stabilize the Myc oncogene to suppress the progression of prostate cancer. 42 A recent study reported on a novel molecular cascade of PHLPP2/CREB/miR-302d that mediates cell cycle progression and anchorageindependent growth. 41 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%

Section: Discussionmentioning

confidence: 99%

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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“…When the cancerous cells are still con ned within the prostate capsule, patients usually receive prostatectomy or radiation therapy and the outcome is well with the 5-yearr survival rate almost 99%. However, many patients are diagnosed after the cancer has spread and the 5-year survival rate of metastatic PCa is only 28% [5]. Although metastatic cancer has been focus of PCa, the mechanisms of PCa malignant progression are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Pinin promotes tumor progression via PI3K/AKT/CREB signaling pathway in prostate cancer

Meng

Zhang²,

Ren

et al. 2020

Preprint

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Abstract Background Pinin (PNN), a desmosome associated protein, was demonstrated to be over-expressed and act as a tumor-promoting factor in ovarian cancer, hepatocellular carcinoma and colorectal cancer. However, the precise role of PNN in prostate cancer is still unknown. Methods The expression levels of PNN were assessed in prostate cancer by qRT-PCR, western blotting and immunohistochemical staining. The other proteins were quantified by western blotting. PNN-depleted cells were produced by infecting with lentivirus bearing short hairpin RNAs against PNN. PNN over-expression was performed by transfecting PNN expression vector. The proliferation of each cell line was assessed by MTS and colony formation assays. Tumors were induced on nude mice by injecting tumor cells subcutaneously. Apoptosis and cell cycle were evaluated by flow cytometry. Transwell and wound healing assay were performed to determined the ability of cell invasion and migration. The TCGA data were analyzed with GEPIA (Gene Expression Profiling Interactive Analysis) and GraphPad Prism. Results Here, we reported that PNN was upregulated in prostate cancer tissues and PNN expression was positively associated with Gleason score, tumor stage and tumor metastasis. PNN promoted cell growth and tumorigenicity in vitro and in vivo, and might modulate cell growth through driving G1/S transition via CDK6, CDK2, and Cyclin D1 in prostate cancer cells. Furthermore, PNN accelerated cell invasion, migration and EMT processes of prostate cancer cells accompanied with the up-regulation of MMP-2, MMP-9, N-cadherin, Vimentin and down-regulation of E-cadherin. Mechanism study demonstrated that the proliferation- and motility-promoting effects of PNN on prostate cancer cells dependent on the activation of PI3K/AKT/CREB signaling, which was reversed by AKT and CREB inhibitors. Conclusions Collectively, these findings indicated that PNN plays important roles in prostate cancer tumorigenesis and progression and it may be a potential therapeutic target for prostate cancer treatment.

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Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth

Weaver

Taylor

Zars

et al. 2020

Journal of Bone and Mineral Research

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Endochondral ossification is tightly controlled by a coordinated network of signaling cascades including parathyroid hormone (PTH). Pleckstrin homology (PH) domain and leucine rich repeat phosphatase 1 (Phlpp1) affects endochondral ossification by suppressing chondrocyte proliferation in the growth plate, longitudinal bone growth, and bone mineralization. As such, Phlpp1−/− mice have shorter long bones, thicker growth plates, and proportionally larger growth plate proliferative zones. The goal of this study was to determine how Phlpp1 deficiency affects PTH signaling during bone growth. Transcriptomic analysis revealed greater PTH receptor 1 (Pth1r) expression and enrichment of histone 3 lysine 27 acetylation (H3K27ac) at the Pth1r promoter in Phlpp1‐deficient chondrocytes. PTH (1‐34) enhanced and PTH (7‐34) attenuated cell proliferation, cAMP signaling, cAMP response element‐binding protein (CREB) phosphorylation, and cell metabolic activity in Phlpp1‐inhibited chondrocytes. To understand the role of Pth1r action in the endochondral phenotypes of Phlpp1‐deficient mice, Phlpp1−/− mice were injected with Pth1r ligand PTH (7‐34) daily for the first 4 weeks of life. PTH (7‐34) reversed the abnormal growth plate and long‐bone growth phenotypes of Phlpp1−/− mice but did not rescue deficits in bone mineral density or trabecular number. These results show that elevated Pth1r expression and signaling contributes to increased proliferation in Phlpp1−/− chondrocytes and shorter bones in Phlpp1‐deficient mice. Our data reveal a novel molecular relationship between Phlpp1 and Pth1r in chondrocytes during growth plate development and longitudinal bone growth. © 2021 American Society for Bone and Mineral Research (ASBMR).

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The PHLPP2 phosphatase is a druggable driver of prostate cancer progression

Abstract: Nowak et al. show that loss of the AKT-inactivating phosphatase PHLPP2 paradoxically blocks prostate tumor growth and metastasis. PHLPP2, they find, is critical for MYC stability, suggesting that PHLPP2 inhibitors may present a therapeutic opportunity to target MYC.

Cited by 39 publications

References 62 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

Pinin promotes tumor progression via PI3K/AKT/CREB signaling pathway in prostate cancer

Pleckstrin homology (PH) domain and Leucine Rich Repeat Phosphatase 1 (Phlpp1) Suppresses Parathyroid Hormone Receptor 1 (Pth1r) Expression and Signaling During Bone Growth

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