The ubiquitin ligase STUB1 suppresses tumorigenesis of renal cell carcinomas through regulating YTHDF1 stability

STIP1 homology and U-box protein 1 (STUB1), a key RING family E3 ubiquitin ligase, plays both oncogenic and tumor-suppressive roles in a variety of human cancers. However, the role and mechanism of STUB1 in clear cell renal cell carcinoma (ccRCC) remains poorly defined. Here, we identified YTHDF1 as a novel STUB1 interactor by affinity purification mass spectrometry (AP-MS). STUB1 polyubiquitylates YTHDF1 and promotes YTHDF1 degradation. STUB1 depletion stabilizes YTHDF1 in renal cancer cells. STUB1-knockdown renal cancer cells exhibit increased migration and invasion in YTHDF1 dependent manner. Further study demonstrates that STUB1 knockdown promoted the tumorigenicity of ccRCC in a xenograft model. Clinically, STUB1 expression is down-regulated in ccRCC tissues, and the low expression level of STUB1 was associated with higher tumor stage and poor overall survival in patients with ccRCC. These findings reveal that STUB1 acts as an E3 ubiquitin ligase and promotes degradation of YTHDF1, and STUB1 inhibits the tumorigenicity of ccRCC through ubiquitinating YTHDF1. Novelty & Impact Statements STUB1 plays both oncogenic and tumor-suppressive roles in a variety of human cancers. Here, the authors demonstrated that STUB1 acts as a tumor suppressor in ccRCC, and the low expression level of STUB1 was associated with higher tumor stage and poor overall survival in patients with ccRCC. In addition, STUB1-knockdown renal cancer cells exhibit increased migration and invasion in YTHDF1 dependent manner. Mechanistically, STUB1 polyubiquitylates YTHDF1 and promotes YTHDF1 degradation.

[1]  Jia Hua Cheng,et al.  HSP90β Impedes STUB1‐Induced Ubiquitination of YTHDF2 to Drive Sorafenib Resistance in Hepatocellular Carcinoma , 2023, Advanced science.

[2]  Honghong Zhou,et al.  STUB1/CHIP: New insights in cancer and immunity. , 2023, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[3]  M. Dong,et al.  O-GlcNAcylation promotes the cytosolic localization of the m6A reader YTHDF1 and colorectal cancer tumorigenesis , 2023, The Journal of biological chemistry.

[4]  Yan Zhou,et al.  CRIP1 suppresses BBOX1‐mediated carnitine metabolism to promote stemness in hepatocellular carcinoma , 2022, The EMBO journal.

[5]  G. Shi,et al.  A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population , 2022, Nature Communications.

[6]  H. He,et al.  N6-methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal cancer. , 2021, Gastroenterology.

[7]  M. Ghosh,et al.  Chaperone-assisted E3 ligase CHIP: A double agent in cancer , 2021, Genes & diseases.

[8]  Haihe Wang,et al.  Adaptor SH3BGRL promotes breast cancer metastasis through PFN1 degradation by translational STUB1 upregulation , 2021, Oncogene.

[9]  Yanqing Ding,et al.  MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly , 2021, Cell Death & Differentiation.

[10]  E. V. Van Allen,et al.  Beyond conventional immune-checkpoint inhibition — novel immunotherapies for renal cell carcinoma , 2021, Nature Reviews Clinical Oncology.

[11]  W. Qu,et al.  Carboxy terminus of HSP70‐interacting protein (CHIP) attenuates the stemness of thyroid cancer cells through decreasing OCT4 protein stability , 2020, Environmental toxicology.

[12]  Hongqiang Cheng,et al.  PDLIM5 inhibits STUB1-mediated degradation of SMAD3 and promotes the migration and invasion of lung cancer cells , 2020, The Journal of Biological Chemistry.

[13]  Jiang Chang,et al.  ANKLE1 N6‐Methyladenosine‐related variant is associated with colorectal cancer risk by maintaining the genomic stability , 2020, International journal of cancer.

[14]  M. Gleave,et al.  p300-Mediated Acetylation of Histone Demethylase JMJD1A Prevents Its Degradation by Ubiquitin Ligase STUB1 and Enhances Its Activity in Prostate Cancer , 2020, Cancer Research.

[15]  Lingqiang Zhang,et al.  Ubiquitin ligase CHIP regulates OTUD3 stability and suppresses tumour metastasis in lung cancer , 2020, Cell Death & Differentiation.

[16]  J. Sheng,et al.  YTHDF1‐mediated translation amplifies Wnt‐driven intestinal stemness , 2020, EMBO reports.

[17]  Guo Ci Teo,et al.  Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma , 2019, Cell.

[18]  D. Tang,et al.  STUB1 suppresseses tumorigenesis and chemoresistance through antagonizing YAP1 signaling , 2019, Cancer science.

[19]  Anthony O. Olarerin-George,et al.  m6A enhances the phase separation potential of mRNA , 2019, Nature.

[20]  J. Meza,et al.  Loss of the Nuclear Pool of Ubiquitin Ligase CHIP/STUB1 in Breast Cancer Unleashes the MZF1-Cathepsin Pro-oncogenic Program. , 2018, Cancer research.

[21]  Y. Zhai,et al.  CHIP/Stub1 regulates the Warburg effect by promoting degradation of PKM2 in ovarian carcinoma , 2017, Oncogene.

[22]  J. Larner,et al.  Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP , 2017, Molecular Cancer Research.

[23]  T. Abbas,et al.  The E3 Ligase CHIP Mediates p21 Degradation to Maintain Radioresistance , 2017, Molecular Cancer Research.

[24]  S. Hewitt,et al.  Molecular Chaperone HSP90 Is Necessary to Prevent Cellular Senescence via Lysosomal Degradation of p14ARF. , 2017, Cancer research.

[25]  Hui Zhang,et al.  PC-1 works in conjunction with E3 ligase CHIP to regulate androgen receptor stability and activity , 2016, Oncotarget.

[26]  Jong-Ryoul Choi,et al.  PARP1 regulates the protein stability and proapoptotic function of HIPK2 , 2016, Cell Death and Disease.

[27]  H-W Lee,et al.  CHIP-mediated degradation of transglutaminase 2 negatively regulates tumor growth and angiogenesis in renal cancer , 2016, Oncogene.

[28]  Hai-rong Chen,et al.  Decreased expression of CHIP leads to increased angiogenesis via VEGF-VEGFR2 pathway and poor prognosis in human renal cell carcinoma , 2015, Scientific Reports.

[29]  M. Ghosh,et al.  Exosome-mediated delivery of the intrinsic C-terminus domain of PTEN protects it from proteasomal degradation and ablates tumorigenesis. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[30]  Jun Yu,et al.  CHIP/Stub1 functions as a tumor suppressor and represses NF-κB-mediated signaling in colorectal cancer. , 2014, Carcinogenesis.

[31]  J. Larner,et al.  Androgen receptor degradation by the E3 ligase CHIP modulates mitotic arrest in prostate cancer cells , 2014, Oncogene.

[32]  Holly McDonough,et al.  The Ubiquitin Ligase CHIP Prevents SirT6 Degradation through Noncanonical Ubiquitination , 2013, Molecular and Cellular Biology.

[33]  H. Aburatani,et al.  Integrated molecular analysis of clear-cell renal cell carcinoma , 2013, Nature Genetics.

[34]  S. Huang,et al.  Expression of carboxyl terminus of Hsp70-interacting protein (CHIP) indicates poor prognosis in human gallbladder carcinoma , 2013, Oncology letters.

[35]  D. Gu,et al.  C Terminus of Hsc70-interacting Protein Promotes Smooth Muscle Cell Proliferation and Survival through Ubiquitin-mediated Degradation of FoxO1* , 2009, The Journal of Biological Chemistry.

[36]  M. Kurosumi,et al.  The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways , 2009, Nature Cell Biology.