HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas

Cancer Res. 2017 Oct 1;77(19):5313-5326. doi: 10.1158/0008-5472.CAN-17-0986. Epub 2017 Aug 14.

Abstract

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313-26. ©2017 AACR.

Publication types

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

MeSH terms

  • Aneuploidy
  • Animals
  • Apoptosis
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology*
  • Cell Cycle
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation
  • Cells, Cultured
  • Chromosomal Instability
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / metabolism
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Hepatocyte Nuclear Factor 1-beta / genetics
  • Hepatocyte Nuclear Factor 1-beta / metabolism*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology*
  • Mad2 Proteins / genetics
  • Mad2 Proteins / metabolism*
  • Mice
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*

Substances

  • BUB1B protein, human
  • Cell Cycle Proteins
  • HNF1B protein, human
  • MAD2L1 protein, human
  • Mad2 Proteins
  • Hepatocyte Nuclear Factor 1-beta
  • Protein-Serine-Threonine Kinases