5uy9 › Citations

Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4.

<div class='caption-title'>BRD4 abundance is positively correlated with PIN1 expression in human gastric cancer tissues</div>
<div class='caption-title'>PIN1 interacts with BRD4 in a phosphorylation-dependent manner in vitro and in vivo</div>
<div class='caption-title'>PIN1 interacts with phosphorylated T204 of BRD4</div>
Hu X, Dong SH, Chen J, Zhou XZ, Chen R, Nair S, Lu KP, Chen LF
OpenAccess logo Oncogene 36 5177-5188 (2017)
Cited: 29 times
EuropePMC logo PMID: 28481868

Abstract

BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4's stability by inhibiting its ubiquitination. PIN1 also catalyses the isomerization of proline 205 of BRD4 and induces its conformational change, which promotes its interaction with CDK9 and increases BRD4's transcriptional activity. Substitution of BRD4 with PIN1-binding-defective BRD4-T204A mutant in gastric cancer cells reduces BRD4's stability, attenuates BRD4-mediated gene expression by impairing its interaction with CDK9 and suppresses gastric cancer cell proliferation, migration and invasion, and tumor formation. Our results identify BRD4 as a new target of PIN1 and suggest that interfering with their interaction could be a potential therapeutic approach for cancer treatment.

Articles - 5uy9 mentioned but not cited (1)

  1. Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase. Chen XR, Igumenova TI. Adv Biol Regul 87 100938 (2023)


Reviews citing this publication (14)

  1. Mission Possible: Advances in MYC Therapeutic Targeting in Cancer. Allen-Petersen BL, Sears RC. BioDrugs 33 539-553 (2019)
  2. Prolyl isomerase Pin1: a promoter of cancer and a target for therapy. Chen Y, Wu YR, Yang HY, Li XZ, Jie MM, Hu CJ, Wu YY, Yang SM, Yang YB. Cell Death Dis 9 883 (2018)
  3. The Functions of BET Proteins in Gene Transcription of Biology and Diseases. Cheung KL, Kim C, Zhou MM. Front Mol Biosci 8 728777 (2021)
  4. BRD4 and MYC: power couple in transcription and disease. Kotekar A, Singh AK, Devaiah BN. FEBS J 290 4820-4842 (2023)
  5. Function of PIN1 in Cancer Development and Its Inhibitors as Cancer Therapeutics. Yu JH, Im CY, Min SH. Front Cell Dev Biol 8 120 (2020)
  6. Oncogenic Hijacking of the PIN1 Signaling Network. Zannini A, Rustighi A, Campaner E, Del Sal G. Front Oncol 9 94 (2019)
  7. Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance. Pu W, Zheng Y, Peng Y. Front Cell Dev Biol 8 168 (2020)
  8. Roles of peptidyl-prolyl isomerase Pin1 in disease pathogenesis. Li J, Mo C, Guo Y, Zhang B, Feng X, Si Q, Wu X, Zhao Z, Gong L, He D, Shao J. Theranostics 11 3348-3358 (2021)
  9. Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy. Chuang HH, Zhen YY, Tsai YC, Chuang CH, Huang MS, Hsiao M, Yang CJ. Biomedicines 9 359 (2021)
  10. Regulation of programmed cell death by Brd4. Hu J, Pan D, Li G, Chen K, Hu X. Cell Death Dis 13 1059 (2022)
  11. Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs. Kliche J, Ivarsson Y. Biochem J 479 1-22 (2022)
  12. Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression. Hu X, Chen LF. Front Cell Dev Biol 8 179 (2020)
  13. Pin1-Catalyzed Conformation Changes Regulate Protein Ubiquitination and Degradation. Jeong J, Usman M, Li Y, Zhou XZ, Lu KP. Cells 13 731 (2024)
  14. Pin1-catalyzed conformational regulation after phosphorylation: A distinct checkpoint in cell signaling and drug discovery. Lu KP, Zhou XZ. Sci Signal 17 eadi8743 (2024)

Articles citing this publication (14)

  1. DUB3 Promotes BET Inhibitor Resistance and Cancer Progression by Deubiquitinating BRD4. Jin X, Yan Y, Wang D, Ding D, Ma T, Ye Z, Jimenez R, Wang L, Wu H, Huang H. Mol Cell 71 592-605.e4 (2018)
  2. Inhibition of BRD4 prevents proliferation and epithelial-mesenchymal transition in renal cell carcinoma via NLRP3 inflammasome-induced pyroptosis. Tan YF, Wang M, Chen ZY, Wang L, Liu XH. Cell Death Dis 11 239 (2020)
  3. BET Inhibition Overcomes Receptor Tyrosine Kinase-Mediated Cetuximab Resistance in HNSCC. Leonard B, Brand TM, O'Keefe RA, Lee ED, Zeng Y, Kemmer JD, Li H, Grandis JR, Bhola NE. Cancer Res 78 4331-4343 (2018)
  4. Pin1 inhibition reverses the acquired resistance of human hepatocellular carcinoma cells to Regorafenib via the Gli1/Snail/E-cadherin pathway. Wang J, Zhang N, Han Q, Lu W, Wang L, Yang D, Zheng M, Zhang Z, Liu H, Lee TH, Zhou XZ, Lu KP. Cancer Lett 444 82-93 (2019)
  5. BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy. Segatto M, Szokoll R, Fittipaldi R, Bottino C, Nevi L, Mamchaoui K, Filippakopoulos P, Caretti G. Nat Commun 11 6108 (2020)
  6. Deficiency of microRNA-628-5p promotes the progression of gastric cancer by upregulating PIN1. Chen Y, Wu Y, Yu S, Yang H, Wang X, Zhang Y, Zhu S, Jie M, Liu C, Li X, Zhou Y, Yang S, Yang Y. Cell Death Dis 11 559 (2020)
  7. Anti-Diabetic Atherosclerosis by Inhibiting High Glucose-Induced Vascular Smooth Muscle Cell Proliferation via Pin1/BRD4 Pathway. Wu Y, Zhang M, Xu C, Chai D, Peng F, Lin J. Oxid Med Cell Longev 2020 4196482 (2020)
  8. Prolyl isomerization of FAAP20 catalyzed by PIN1 regulates the Fanconi anemia pathway. Wang J, Chan B, Tong M, Paung Y, Jo U, Martin D, Seeliger M, Haley J, Kim H. PLoS Genet 15 e1007983 (2019)
  9. Hyperglycemia induces gastric carcinoma proliferation and migration via the Pin1/BRD4 pathway. Yu J, Hu D, Wang L, Fan Z, Xu C, Lin Y, Chen X, Lin J, Peng F. Cell Death Discov 8 224 (2022)
  10. PIN1P1 is activated by CREB1 and promotes gastric cancer progression via interacting with YBX1 and upregulating PIN1. Wang YW, Zhu WJ, Ma RR, Tian YR, Chen X, Gao P. J Cell Mol Med 28 e18022 (2024)
  11. Targeting peptidyl-prolyl isomerase 1 in experimental pulmonary arterial hypertension. Rai N, Sydykov A, Kojonazarov B, Wilhelm J, Manaud G, Veeroju S, Ruppert C, Perros F, Ghofrani HA, Weissmann N, Seeger W, Schermuly RT, Novoyatleva T. Eur Respir J 60 2101698 (2022)
  12. DSC2 Suppresses the Metastasis of Gastric Cancer through Inhibiting the BRD4/Snail Signaling Pathway and the Transcriptional Activity of β-Catenin. Sun C, Wang L, Du DD, Ji JB, Yang XX, Yu BF, Shang PF, Guo XL. Oxid Med Cell Longev 2022 4813571 (2022)
  13. Methylation of BRD4 by PRMT1 regulates BRD4 phosphorylation and promotes ovarian cancer invasion. Liu Y, Liu H, Ye M, Jiang M, Chen X, Song G, Ji H, Wang ZW, Zhu X. Cell Death Dis 14 624 (2023)
  14. A novel bivalent interaction mode underlies a non-catalytic mechanism for Pin1-mediated protein kinase C regulation. Chen XR, Dixit K, Yang Y, McDermott MI, Imam HT, Bankaitis VA, Igumenova TI. Elife 13 e92884 (2024)


Quick links