p27 transcriptionally coregulates cJun to drive programs of tumor progression

Yoon, Hyunho; Kim, Minsoon; Jang, Keum‐Il; Shin, Moo Whan; Besser, Alexandra H.; Xiao, Xue; Zhao, Daqing; Wander, Seth A.; Briegel, Karoline J.; Morey, Lluís; Minn, Andy J.; Slingerland, Joyce M.

doi:10.1073/pnas.1817415116

Cited by 36 publications

(59 citation statements)

References 64 publications

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“…S2A; Supplementary Tables S4 and S5). Of note, we also identified other pathways with reported activities in the regulation of invasion, such as p27, FAS, and RAC, although their prevalence in the analysis and their documented association to this phenotype were minor (26)(27)(28)(29).…”

Section: Resultsmentioning

confidence: 74%

PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

et al. 2019

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The PPARg coactivator 1 alpha (PGC1a) is a prostate tumor suppressor that controls the balance between anabolism and catabolism. PGC1A downregulation in prostate cancer is causally associated with the development of metastasis. Here we show that the transcriptional complex formed by PGC1a and estrogen-related receptor 1 alpha (ERRa) controls the aggressive properties of prostate cancer cells. PGC1a expression significantly decreased migration and invasion of various prostate cancer cell lines. This phenotype was consistent with remarkable cytoskeletal remodeling and inhibition of integrin alpha 1 and beta 4 expression, both in vitro and in vivo. CRISPR/ Cas9-based deletion of ERRa suppressed PGC1a regulation of cytoskeletal organization and invasiveness. Mechanistically, PGC1a expression decreased MYC levels and activity prior to inhibition of invasiveness. In addition, PGC1a and ERRa associated at the MYC promoter, supporting the inhibitory activity PGC1a. The inverse correlation between PGC1a-ERRa activity and MYC levels was corroborated in multiple prostate cancer datasets. Altogether, these results support that PGC1a-ERRa functions as a tumor-suppressive transcriptional complex through the regulation of metabolic and signaling events. Significance: These findings describe how downregulation of the prostate tumor suppressor PGC1 drives invasiveness and migration of prostate cancer cells.

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Section: Resultsmentioning

confidence: 74%

PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

et al. 2019

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“…Low p27 expression has been correlated with an increased tumor stage and shorter overall survival by some investigators [27,28], whereas others see no predictive value of p27 [29,30], or even observe high p27 associated with poor prognosis [31]. Increased p27 has also been associated with loss of bladder cancer cell proliferation in several in vitro experiments [32], whereas others point to a role of p27 in activating epithelial-mesenchymal transformation [33] and forcing tumor cell migration and invasion [34]. p27 was only moderately diminished by SFN and the SFN-everolimus combination.…”

Section: Discussionmentioning

confidence: 99%

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

Justin

Rutz

Maxeiner

et al. 2020

IJMS

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Progressive bladder cancer growth is associated with abnormal activation of the mammalian target of the rapamycin (mTOR) pathway, but treatment with an mTOR inhibitor has not been as effective as expected. Rather, resistance develops under chronic drug use, prompting many patients to lower their relapse risk by turning to natural, plant-derived products. The present study was designed to evaluate whether the natural compound, sulforaphane (SFN), combined with the mTOR inhibitor everolimus, could block the growth and proliferation of bladder cancer cells in the short- and long-term. The bladder cancer cell lines RT112, UMUC3, and TCCSUP were exposed short- (24 h) or long-term (8 weeks) to everolimus (0.5 nM) or SFN (2.5 µM) alone or in combination. Cell growth, proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins were evaluated. siRNA blockade was used to investigate the functional impact of the proteins. Short-term application of SFN and/or everolimus resulted in significant tumor growth suppression, with additive inhibition on clonogenic tumor growth. Long-term everolimus treatment resulted in resistance development characterized by continued growth, and was associated with elevated Akt-mTOR signaling and cyclin-dependent kinase (CDK)1 phosphorylation and down-regulation of p19 and p27. In contrast, SFN alone or SFN+everolimus reduced cell growth and proliferation. Akt and Rictor signaling remained low, and p19 and p27 expressions were high under combined drug treatment. Long-term exposure to SFN+everolimus also induced acetylation of the H3 and H4 histones. Phosphorylation of CDK1 was diminished, whereby down-regulation of CDK1 and its binding partner, Cyclin B, inhibited tumor growth. In conclusion, the addition of SFN to the long-term everolimus application inhibits resistance development in bladder cancer cells in vitro. Therefore, sulforaphane may hold potential for treating bladder carcinoma in patients with resistance to an mTOR inhibitor.

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“…P27 is an unstructured multifunctional protein that affects a variety of biological processes from cell cycle regulation to cell migration and transcriptional regulation [36]. Notably, it has been reported that in addition to the loss of nuclear p27, the increase of cytoplasmic p27 in many human tumors is usually related to the invasiveness of tumors and the poor prognosis of patients [37,38]. Our results showed that the expression of p21 in Caski cells treated with TGF-β was significantly increased, which may be related to the inhibition of cell cycle arrest in G2/M phase.…”

Section: Discussionmentioning

confidence: 99%

C-phycocyanin inhibits epithelial-to-mesenchymal transition in Caski cells

Liu

Han

et al. 2020

Cancer Cell Int

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Background: In cervical cancer, most patients die of metastasis. The epithelial-to-mesenchymal transition (EMT) is a pivotal and intricate process that increases the metastatic potential of cervical cancer. C-phycocyanin (C-PC) is a natural marine product isolated and purified from Spirulina platensis, has been investigated that has anti-cancer function. The aim of this study was to explore the inhibitory effect of C-phycocyanin on the migration and invasion of cervical cancer cells induced by transforming growth factor-β1 (TGF-β1), so as to provide a new idea for the treatment and prognosis of cervical cancer. Methods: A wound-healing assay, an invasion assay, immunofluorescence assay, western blot, flow cytometry and real-time reverse transcriptione polymerase chain reaction were explored in cervical cancer Caski cell lines. TGF-β/ smad signaling pathway was evaluated of in Caski cell lines. Results: Our study indicated that TGF-β1 induced EMT in cervical cancer cells. C-phycocyanin inhibited EMT in Caski cells by down-regulating N-cadherin and up-regulating E-cadherin protein expression. Furthermore, C-phycocyanin could inhibit the expression and proteins Twist, Snail and Zeb1 transcription factors related to EMT. In addition, C-phycocyanin could inhibit the migration and invasion of Caski cells induced by TGF-β1. Besides, C-phycocyanin inhibited EMT through TGF-β/smads signaling pathway. We also found C-phycocyanin induced cell cycle G0/G1 arrest by decreasing protein expression levels of Cyclin D1 and p27. Conclusions: C-phycocyanin reversed TGF-β1-induced epithelial-to-mesenchymal transition in cervical cancer cells and down-regulated the TGF-β/samd signaling pathway induced G0/G1 arrest of tumor cell cycle.

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p27 transcriptionally coregulates cJun to drive programs of tumor progression

Cited by 36 publications

References 64 publications

PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

PGC1α Suppresses Prostate Cancer Cell Invasion through ERRα Transcriptional Control

Chronic Sulforaphane Administration Inhibits Resistance to the mTOR-Inhibitor Everolimus in Bladder Cancer Cells

C-phycocyanin inhibits epithelial-to-mesenchymal transition in Caski cells

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