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Low cytoplasmic NUB1 protein exerts hypoxic cell death with poorer prognosis in oestrogen receptor negative breast cancer patients

Tan KL 1 , Haider S 2 , Zois CE 3 , Hu J 4 , Turley H 3 , Leek R 3 Show all authors , Buffa F 5 , Acuto O 6 , Harris AL 3 , Pezzella F 7

Affiliations 

  • 1 Tumour Pathology Laboratory, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK; Faculty of Medicine and Health Sciences, Universiti Sains Islam Malaysia (USIM), Persiaran Ilmu, Putra Nilai, 71800 Nilai, Negeri Sembilan, Malaysia. Electronic address: kaliong_tan@usim.edu.my
  • 2 Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK; Computational Biology and Integrative Genomics, Department of Oncology, Old Road Campus Research Building, Roosevelt Drive Oxford, University of Oxford, UK; The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK. Electronic address: Syed.Haider@icr.ac.uk
  • 3 Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ, UK
  • 4 Tumour Pathology Laboratory, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
  • 5 Computational Biology and Integrative Genomics, Department of Oncology, Old Road Campus Research Building, Roosevelt Drive Oxford, University of Oxford, UK
  • 6 Laboratory of T-cell signalling, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK
  • 7 Tumour Pathology Laboratory, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Electronic address: francesco.pezzella@ndcls.ox.ac.uk
Transl Oncol, 2024 Nov;49:102106.
PMID: 39182365 DOI: 10.1016/j.tranon.2024.102106

Abstract

Current prognostic biomarkers fall short in stratifying Oestrogen receptor (ER)-negative breast cancer patients regarding tumour progression risk at diagnosis. The role of AIPL1 in activating its tumour suppressor client protein, NEDD8 Ultimate Buster-1 (NUB1) remains unknown in cancer. Our study demonstrated how downregulated AIPL1 results in the deactivated NUB1 protein under hypoxic conditions. We examined the AIPL1-NUB1 pathwayin vitro using cell lines i.e. MCF-7, MDA-MB-231, RCC4 etc. NUB1 expression was assessed using Oncomine, and cBioPortal was performed to assess NUB1's prognostic significance in human cancers. In the John Radcliffe Hospital cohort (n = 122), immunohistochemistry analysis revealed downregulated AIPL1 (Log2 fold change=-0.28; p < 0.001) and upregulated NUB1 transcripts (Log2 fold change=0.59; p < 0.001) compared to adjacent normal tissues. In severe chronic hypoxia, multimerised AIPL1 localisedin the cytoplasm while NUB1 protein migrated to the nucleus, where the absence of NUB1 nuclear localisation led to cell cycle arrest. Biopsies showed that patients with lower cytoplasmic NUB1 expression (n = 57) had poorer overall survival compared to those with higher cytoplasmic expression (n = 57), HR=1.78; 95 % CI=1.01-3.35, p = 0.048. Low NUB1 protein levels in both normoxic and hypoxic conditions were associated with cell cycle arrest and upregulation ofp21 and p27 in breast cancer cell lines, correlating significantly withpoorer survival outcomes in all breast cancer and ER-negative breast cancer patients.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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