The Deubiquitinase USP46 Is Essential for Proliferation and Tumor Growth of HPV-Transformed Cancers

Mol Cell. 2018 Dec 6;72(5):823-835.e5. doi: 10.1016/j.molcel.2018.09.019. Epub 2018 Nov 8.

Abstract

High-risk human papilloma viruses (HPVs) cause cervical, anal, and oropharyngeal cancers, unlike the low-risk HPVs, which cause benign lesions. E6 oncoproteins from the high-risk strains are essential for cell proliferation and transformation in HPV-induced cancers. We report that a cellular deubiquitinase, USP46, is selectively recruited by the E6 of high-risk, but not low-risk, HPV to deubiqutinate and stabilize Cdt2/DTL. Stabilization of Cdt2, a component of the CRL4Cdt2 E3 ubiquitin ligase, limits the level of Set8, an epigenetic writer, and promotes cell proliferation. USP46 is essential for the proliferation of HPV-transformed cells, but not of cells without HPV. Cdt2 is elevated in human cervical cancers and knockdown of USP46 inhibits HPV-transformed tumor growth in xenografts. Recruitment of a cellular deubiquitinase to stabilize key cellular proteins is an important activity of oncogenic E6, and the importance of E6-USP46-Cdt2-Set8 pathway in HPV-induced cancers makes USP46 a target for the therapy of such cancers.

Keywords: Cdt2; E6; HPV; USP46; cervical cancer; deubiquitinase; oncogenic virus.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle
  • Cell Line, Tumor
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endopeptidases / genetics*
  • Endopeptidases / metabolism
  • Female
  • Gene Expression Regulation
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Host-Pathogen Interactions / genetics
  • Human papillomavirus 16 / genetics*
  • Human papillomavirus 16 / metabolism
  • Human papillomavirus 16 / pathogenicity
  • Human papillomavirus 18 / genetics*
  • Human papillomavirus 18 / metabolism
  • Human papillomavirus 18 / pathogenicity
  • Humans
  • Injections, Intralesional
  • Mice
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Viral / genetics
  • Oncogene Proteins, Viral / metabolism
  • Papillomavirus Infections / enzymology
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Uterine Cervical Neoplasms / enzymology
  • Uterine Cervical Neoplasms / genetics*
  • Uterine Cervical Neoplasms / pathology
  • Uterine Cervical Neoplasms / virology
  • Xenograft Model Antitumor Assays

Substances

  • DNA-Binding Proteins
  • DTL protein, human
  • E6 protein, Human papillomavirus type 16
  • E6 protein, Human papillomavirus type 18
  • IL17RB protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Viral
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human
  • Ubiquitin-Protein Ligases
  • Endopeptidases
  • ubiquitin-specific peptidase 46, human