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Structural Insights into BET Client Recognition of Endometrial and Prostate Cancer-Associated SPOP Mutants.

Ostertag MS, Hutwelker W, Plettenburg O, Sattler M, Popowicz GM
J Mol Biol 431 2213-2221 (2019)
Related entries: 6i41, 6i5p, 6i68

Cited: 9 times
EuropePMC logo PMID: 31026449

Abstract

BET proteins such as BRD3 are oncogenic transcriptional coactivators. SPOP binding triggers their proteasomal degradation. In both endometrial and prostate cancers, SPOP mutations occur in the MATH domain, but with opposed influence on drug susceptibility. In prostate cancer, SPOP mutations presumably cause increased BET levels, decreasing BET inhibitor drug susceptibility. As opposed, in endometrial cancer, decreased BET levels concomitant with higher BET inhibitor drug susceptibility were observed. Here, we present the to our knowledge first co-crystal structure of SPOP and a bromodomain containing protein (BRD3). Our structural and biophysical data confirm the suggested loss-of-function in prostate cancer-associated SPOP mutants and provide mechanistic explanation. As opposed to previous literature, our data on endometrial cancer-associated SPOP mutants do not show altered binding behavior compared to wild-type SPOP, indicating a more complex regulatory mechanism. SPOP mutation screening may thus be considered a valuable personalized medicine tool for effective antitumor therapy.

Reviews citing this publication (3)

  1. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. Ishida T, Ciulli A. SLAS Discov 26 484-502 (2021)
  2. The E3 Ligases in Cervical Cancer and Endometrial Cancer. Zhai F, Wang J, Yang W, Ye M, Jin X. Cancers (Basel) 14 5354 (2022)
  3. BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications. To KKW, Xing E, Larue RC, Li PK. Molecules 28 3043 (2023)

Articles citing this publication (6)

  1. ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication. Wang D, Ma J, Botuyan MV, Cui G, Yan Y, Ding D, Zhou Y, Krueger EW, Pei J, Wu X, Wang L, Pei H, McNiven MA, Ye D, Mer G, Huang H. Sci Adv 7 eabd9208 (2021)
  2. Intrinsically disordered substrates dictate SPOP subnuclear localization and ubiquitination activity. Usher ET, Sabri N, Rohac R, Boal AK, Mittag T, Showalter SA. J Biol Chem 296 100693 (2021)
  3. Exploration of the Tumor Mutational Burden as a Prognostic Biomarker and Related Hub Gene Identification in Prostate Cancer. Wang L, Yao Y, Xu C, Wang X, Wu D, Hong Z. Technol Cancer Res Treat 20 15330338211052154 (2021)
  4. Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens. Wright S, Hu J, Wang H, Hyle J, Zhang Y, Du G, Konopleva MY, Kornblau SM, Djekidel MN, Rosikiewicz W, Xu B, Lu R, Yang JJ, Li C. Proc Natl Acad Sci U S A 120 e2220134120 (2023)
  5. Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation. Cuneo MJ, O'Flynn BG, Lo YH, Sabri N, Mittag T. Mol Cell 83 731-745.e4 (2023)
  6. SPOP Inhibition of Endometrial Carcinoma and Its Clinicopathological Relationship. Zhu Q, Zhang G, Tang M, Zheng R, Gan H. Appl Bionics Biomech 2022 5721630 (2022)


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