CoChat
Sign Up
Cited by 74Cytokine Signaling Pathways and InteractionsProtein Tyrosine PhosphatasesTGF-β signaling in diseases

Targeting oncogenic transcription factors: therapeutic implications of endogenous STAT inhibitors

Open access
Heppler, Lisa N., Frank, David A.·2017·Trends in Cancer
DOI 10.1016/j.trecan.2017.10.004PMC PMC5727919
Open this paper in CoChat — free account

Abstract

Misregulation of transcription factors, including signal transducer and activator of transcription (STAT) proteins, leads to inappropriate gene expression patterns that can promote tumor initiation and progression. Under physiologic conditions, STAT signaling is stimulus dependent and tightly regulated by endogenous inhibitors, namely, suppressor of cytokine signaling (SOCS) proteins, phosphatases, and protein inhibitor of activated STAT (PIAS) proteins. However, in tumorigenesis, STAT proteins become constitutively active and promote the expression of progrowth and prosurvival genes. Although STAT activation has been widely implicated in cancer, therapeutic STAT inhibitors are still largely absent from the clinic. This review dissects the mechanisms of action of two families of endogenous STAT inhibitors, the SOCS and PIAS families, to potentially inform the development of novel therapeutic inhibitors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.trecan.2017.10.004

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or SOCS protein members.

    “Other approaches currently underway involve modulation of autoregulators of STAT3 activity, such as strategies to activate protein phosphatases, members of the protein inhibitors of activated STAT family, or suppressor of cytokine signaling (SOCS) protein members (Heppler and Frank, 2017; Durham et al., 2019).”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Heppler and Frank, 2017

    The Therapeutic Implications of Endogenous STAT Inhibitors section (page unavailable) describes efforts to restore SOCS and PIAS expression and mimic SOCS1 activity. The Concluding Remarks (page unavailable) instead treat investigation of STAT phosphatases as a potential route to future therapies; they do not describe strategies to activate phosphatases as currently underway. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 76

  1. [1]Lee TI Young RA 2013 Transcriptional regulation and its misregulation in disease Cell 152 1237 1251 23498934 PMC3640494
  2. [2]Bhagwat AS Vakoc CR 2015 Targeting Transcription Factors in Cancer Trends in Cancer 1 53 65 26645049 PMC4669894
  3. [3]Yeh JE 2013 Targeting transcription factors: promising new strategies for cancer therapy Curr. Opin. Oncol 25 652 658 24048019
  4. [4]Miklossy G 2013 Therapeutic modulators of STAT signalling for human diseases Nat. Rev. Drug Discov 12 611 629 23903221 PMC4038293
  5. [5]Buettner R 2002 Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention Clin. Cancer Res 8 945 954 11948098
  6. [6]Vainchenker W Constantinescu SN 2013 JAK/STAT signaling in hematological malignancies Oncogene 32 2601 2613 22869151
  7. [7]Quintás-Cardama A Verstovsek S 2013 Molecular pathways: JAK/STAT pathway: Mutations, inhibitors, and resistance Clin. Cancer Res 19 1933 1940 23406773 PMC5021219
  8. [8]Villarino AV 2015 Mechanisms of Jak/STAT Signaling in Immunity and Disease J. Immunol 194 21 27 25527793 PMC4524500
  9. [9]Yu H 2009 STATs in cancer inflammation and immunity: a leading role for STAT3 Nat. Rev. Cancer 9 798 809 19851315 PMC4856025
  10. [10]Kaler P 2014 The Role of STAT1 for Crosstalk between Fibroblasts and Colon Cancer Cells Front. Oncol 4 88 24818101 PMC4012204
  11. [11]Wee ZN 2014 EZH2-mediated inactivation of IFN-γ-JAK-STAT1 signaling is an effective therapeutic target in MYC-driven prostate cancer Cell Rep 8 204 216 24953652
  12. [12]Kharma B 2014 STAT1 drives tumor progression in serous papillary endometrial cancer Cancer Res 74 6519 6530 25267067
  13. [13]Kortylewski M 2005 Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity Nat. Med 11 1314 1321 16288283
  14. [14]Yu H 2014 Revisiting STAT3 signalling in cancer: new and unexpected biological functions Nat. Rev. Cancer 14 736 746 25342631
  15. [15]Avalle L 2012 STAT1 and STAT3 in tumorigenesis: A matter of balance Jak-Stat 1 65 72 24058752 PMC3670295
  16. [16]Nivarthi H 2016 The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth Oncotarget 5 51096 51106 PMC5239461 27191495
  17. [17]Hoelbl A 2010 Stat5 is indispensable for the maintenance of Bcr/Abl-positive leukaemia EMBO Mol. Med 2 98 110 20201032 PMC2906698
  18. [18]Warsch W 2011 High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia Blood 117 3409 3420 21220747
  19. [19]Warsch W 2012 STAT5 triggers BCR-ABL1 mutation by mediating ROS production in chronic myeloid leukaemia Oncotarget 3 1669 1687 23458731 PMC3681503
  20. [20]Leong PL 2002 Differential function of STAT5 isoforms in head and neck cancer growth control Oncogene 11 2846 2853 11973644
  21. [21]Walker SR 2014 Distinct roles of STAT3 and STAT5 in the pathogenesis and targeted therapy of breast cancer Mol. Cell. Endocrinol 382 616 621 23531638 PMC3732813
  22. [22]Yu H Jove R 2004 The STATs of cancer — new molecular targets come of age Nat. Rev. Cancer 4 97 105 14964307
  23. [24]Furtek SL 2016 Strategies and Approaches of Targeting STAT3 for Cancer Treatment ACS Chem. Biol 11 308 318 26730496
  24. [25]Furqan M 2013 STAT inhibitors for cancer therapy J. Hematol. Oncol 6 90 24308725 PMC4029528
  25. [26]Dorritie KA 2014 STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention Leukemia 28 248 257 23797472
  26. [27]Nelson EA 2008 Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3 Blood 112 5095 5102 18824601 PMC2597607
  27. [28]Takakura A 2011 Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways Hum. Mol. Genet 20 4143 4154 21821671 PMC3188991
  28. [29]Nelson EA 2011 The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors Blood 117 3421 3429 21233313 PMC3069678
  29. [30]Nelson EA 2012 The STAT5 Inhibitor Pimozide Displays Efficacy in Models of Acute Myelogenous Leukemia Driven by FLT3 Mutations Genes Cancer 3 503 511 23264850 PMC3527989
  30. [31]Mahony R 2016 SOCS3 revisited: a broad regulator of disease, now ready for therapeutic use? Cell. Mol. Life Sci 73 3323 3336 27137184 PMC11108554
  31. [32]Linossi EM 2013 Suppression of cytokine signaling: The SOCS perspective Cytokine Growth Factor Rev 24 241 248 23545160 PMC3816980
  32. [33]Lavens D 2006 Review: Negative regulation of leptin receptor signalling Eur. Cytokine Netw 17 211 219 17194642
  33. [34]Lavens D 2006 A complex interaction pattern of CIS and SOCS2 with the leptin receptor J. Cell Sci 119 2214 2224 16684815
  34. [35]Ram PA Waxman DJ 1999 SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms J. Biol. Chem 274 35553 35561 10585430
  35. [36]Uyttendaele I 2007 Mammalian protein-protein interaction trap (MAPPIT) analysis of STAT5, CIS, and SOCS2 interactions with the growth hormone receptor Mol. Endocrinol 21 2821 2831 17666591
  36. [37]Endo T 2003 CIS1 Interacts with the Y532 of the Prolactin Receptor and Suppresses Prolactin-Dependent STAT5 Activation J. Biol. Chem 133 109 113 12761205
  37. [38]Ahmad A Ahmad R 2012 Understanding the mechanism of hepatic fibrosis and potential therapeutic approaches Saudi J. Gastroenterol 18 155 167 22626794 PMC3371417
  38. [39]Coyaud E 2015 BioID-based Identification of Skp Cullin F-box (SCF)β-TrCP1/2 E3 Ligase Substrates Mol. Cell. Proteomics 14 1781 1795 25900982 PMC4587326
  39. [40]Haglund K 2003 Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation Nat. Cell Biol 5 461 466 12717448
  40. [41]Irandoust MI 2007 Suppressor of cytokine signaling 3 controls lysosomal routing of G-CSF receptor EMBO J 26 1782 1793 17363902 PMC1847666
  41. [42]Croker BA 2008 SOCS regulation of the JAK/STAT signalling pathway Semin. Cell Dev. Biol 19 414 422 18708154 PMC2597703
  42. [43]Vesterlund M 2011 The SOCS2 ubiquitin ligase complex regulates growth hormone receptor levels PLoS One 6 1 10 PMC3183054 21980433
  43. [45]Yoshimura A Yasukawa H 2012 JAK’s SOCS: A Mechanism of Inhibition Immunity 36 157 159 22365659
  44. [46]Babon JJ 2012 Suppression of Cytokine Signaling by SOCS3: Characterization of the Mode of Inhibition and the Basis of Its Specificity Immunity 36 239 250 22342841 PMC3299805
  45. [47]Inagaki-Ohara K 2013 SOCS, inflammation, and cancer Jak-Stat 2 e24053 24069550 PMC3772102
  46. [48]Zhang X 2015 Upregulation of miR-572 transcriptionally suppresses SOCS1 and p21 and contributes to human ovarian cancer progression Oncotarget 6 15180 93 25893382 PMC4558144
  47. [49]Das R 2017 MicroRNA-194 promotes prostate cancer metastasis by inhibiting SOCS2 Cancer Res 77 1021 1034 28011622
  48. [50]Patel K 2014 MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression Cancer Lett 347 54 64 24491408 PMC3972339
  49. [51]Shah MY 2016 microRNA Therapeutics in Cancer — An Emerging Concept EBioMedicine 12 34 42 27720213 PMC5078622
  50. [52]Shuai K 2006 Regulation of cytokine signaling pathways by PIAS proteins Cell Res 16 196 202 16474434
  51. [53]Rabellino A 2017 The Role of PIAS SUMO E3-Ligases in Cancer Cancer Res 77 1542 1547 28330929 PMC5380518
  52. [54]Shuai K Liu B 2005 Regulation of gene-activation pathways by PIAS proteins in the immune system Nat. Rev. Immunol 5 593 605 16056253
  53. [55]Yuan J 2016 Multiple regulation pathways and pivotal biological functions of STAT3 in cancer Sci. Rep 5 1 10 PMC4668392 26631279
  54. [57]Liu B 1998 Inhibition of Stat1-mediated gene activation by PIAS1 Proc. Natl. Acad. Sci 95 10626 10631 9724754 PMC27945
  55. [58]Pan C 2016 Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings Oncotarget 7 60395 60406 27486982 PMC5312391
  56. [59]Palvimo JJ 2007 PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription Biochem. Soc. Trans 35 1405 1408 18031232
  57. [60]Hendriks IA 2014 Uncovering global SUMOylation signaling networks in a site-specific manner Nat. Struct. Mol. Biol 21 927 936 25218447 PMC4259010
  58. [61]Matic I 2010 Site-Specific Identification of SUMO-2 Targets in Cells Reveals an Inverted SUMOylation Motif and a Hydrophobic Cluster SUMOylation Motif Mol. Cell 39 641 652 20797634
  59. [62]Hornbeck PV 2015 PhosphoSitePlus, 2014: Mutations, PTMs and recalibrations Nucleic Acids Res 43 D512 D520 25514926 PMC4383998
  60. [63]Jakobs A 2007 Ubc9 fusion-directed SUMOylation (UFDS): a method to analyze function of protein SUMOylation Nat. Methods 4 245 250 17277783
  61. [64]Zimnik S 2009 Mutually exclusive STAT1 modifications identified by Ubc9/substrate dimerization-dependent SUMOylation Nucleic Acids Res 37 1 7 19174562 PMC2651805
  62. [65]Grönholm J 2012 Structure-function analysis indicates that sumoylation modulates DNA-binding activity of STAT1 BMC Biochem 13 20 23043228 PMC3532225
  63. [66]Zhou Z 2016 SUMOylation and SENP3 regulate STAT3 activation in head and neck cancer Oncogene 35 5826 5838 27181202 PMC5116054
  64. [67]Dagvadorj A 2010 N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells Int. J. Biochem. Cell Biol 42 2037 2046 20854925 PMC2982800
  65. [68]Puhr M 2014 PIAS1 is a crucial factor for prostate cancer cell survival and a valid target in docetaxel resistant cells Oncotarget 5 12043 12056 25474038 PMC4322998
  66. [69]Niwa Y 2005 Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma Oncogene 24 6406 6417 16007195
  67. [70]Xiong H 2012 Trichostatin A, a histone deacetylase inhibitor, suppresses JAK2/STAT3 signaling via inducing the promoter-associated histone acetylation of SOCS1 and SOCS3 in human colorectal cancer cells Mol. Carcinog 51 174 184 21520296
  68. [71]Chen C 2013 Pure curcumin increases the expression of SOCS1 and SOCS3 in myeloproliferative neoplasms through suppressing class I histone deacetylases Carcinogenesis 34 1442 1449 23430957
  69. [72]Gao S 2013 Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms Exp. Hematol 41 261 270 23111066
  70. [73]Brantley EC 2008 Loss of protein inhibitors of activated STAT-3 expression in glioblastoma multiforme tumors: Implications for STAT-3 activation and gene expression Clin. Cancer Res 14 4694 4704 18676737 PMC3886729
  71. [74]Manton CA 2016 Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo Sci. Rep 6 1 13 26804704 PMC4726202
  72. [75]Flowers LO 2004 Characterization of a Peptide Inhibitor of Janus Kinase 2 That Mimics Suppressor of Cytokine Signaling 1 Function J. Immunol 172 7510 7518 15187130
  73. [76]Flowers LO 2005 A SOCS-1 peptide mimetic inhibits both constitutive and IL-6 induced activation of STAT3 in prostate cancer cells Oncogene 24 2114 2120 15688010
  74. [77]Madonna S 2013 Therapeutical potential of a peptide mimicking the SOCS1 kinase inhibitory region in skin immune responses Eur. J. Immunol 43 1883 1895 23592500
  75. [78]Doti N 2012 New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries Biochem. J 443 231 240 22166051
  76. [79]Levy DE Darnell JE 2002 Signalling: STATs: transcriptional control and biological impact Nat. Rev. Mol. Cell Biol 3 651 662 12209125

Cited by

Sorted by citations

Authors
Heppler, L. N., & Frank, D. A.
Affiliations
Brigham and Women's Hospital (US)
Corresponding author
Frank, David A.
ORCID
Venue
Trends in Cancer
Publisher
Elsevier BV
Published
2017-12
Volume
3
Issue
12
Pages
816-827
ISSN
  • 2405-8025 (ISSN-L)
  • 2405-8033
DOI
10.1016/j.trecan.2017.10.004
PMC
PMC5727919
OpenAlex
W2768055114
Cited by
74
References
4
Citations by year
2025: 4 · 2024: 12 · 2023: 9 · 2022: 6 · 2021: 18 · 2020: 12 · 2019: 9 · 2018: 4
FWCI
0.72
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Trends in cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA160979)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
STAT signaling, suppressor of cytokine signaling, phosphatase, oncogenic transcription factor, tumor progression, cancer therapy, gene expression regulation
MeSH terms
Antineoplastic Agents, Humans, Neoplasms, Cell Proliferation, STAT Transcription Factors, Suppressor of Cytokine Signaling Proteins, Protein Inhibitors of Activated STAT, Carcinogenesis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review