VHL, HIF and epigenetic modifications in clear cell renal cancer

In an earlier blog post, Vicki discussed a paper by Dalgliesh et al. (2010), which describes the identification of mutations in a variety of histone modifying genes in clear cell renal cell carcinoma (ccRCC). One of the genes identified codes for a tri-methylation-specific histone H3 lysine 4 (H3K4Me3) demethylase called JARID1C. Recent work by Niu et al. (2011) has now taken this finding further by showing that JARID1C is a potential HIF target gene downstream of VHL, which not only attenuates H3K4Me3 levels and gene expression, but may also suppress tumour growth.

In this study, reduced levels of H3K4Me3 were seen in two VHL-null ccRCC cell lines (786-O and RCC4) when compared to their VHL-positive controls. Moreover, JARID1C mRNA and protein levels were higher in VHL-null 786-O cells than in VHL-positive controls, and shRNA knockdown of JARID1C in this cell line confirmed that these two phenomena were linked.

The authors then showed that shRNA knockdown of HIF2α in VHL-null 786-O cells led to increased levels of H3K4Me3, as did shRNA knockdown of HIF1β and HIF2α (but not HIF1α) in the VHL-null RCC4 cell line. shRNA knockdown of HIF2α in VHL-null 786-O cells also led to decreased amounts of JARID1C mRNA and protein, and transcriptionally active HIF2α in VHL-positive 786-O and ACHN cells led to increased levels of JARID1C and decreased levels of H3K4Me3. Interestingly, experiments in Ren-01 cells showed that HIF1α also influenced JARID1C expression, unlike the aforementioned cell lines. Collectively, these results suggest that HIF signalling plays an important role in the induction of JARID1C, but that the exact factors involved are most likely cell-type specific.

What impact do these changes in JARID1C expression have on transcription and tumourigenesis? Niu et al. demonstrated that shRNA knockdown of JARID1C in VHL-null 786-O cells led to increased expression of IGFBP3, GDF15, DNAJC12 and COL6A1, which correlated with increased levels of H3K4Me3 at their promoters. The authors also showed that VHL-null 786-O cells in which JARID1C was knocked-down formed larger tumours than control cells when injected into nude mice, suggesting a tumour suppressive role for this protein.

To conclude, this work builds upon the data from the sequencing experiments by Dalgliesh et al. and aims to explain how mutations in JARID1C could affect tumour growth. Additionally, from another standpoint, it would be of particular interest to see if similar mechanisms are at play in BHD syndrome, as FLCN has also been observed to be associated with HIF signalling (Preston et al., 2010).

 

  • Dalgliesh, G., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P., Forbes, S., Jia, M., Jones, D., Knott, H., Kok, C., Lau, K., Leroy, C., Lin, M., McBride, D., Maddison, M., Maguire, S., McLay, K., Menzies, A., Mironenko, T., Mulderrig, L., Mudie, L., O’Meara, S., Pleasance, E., Rajasingham, A., Shepherd, R., Smith, R., Stebbings, L., Stephens, P., Tang, G., Tarpey, P., Turrell, K., Dykema, K., Khoo, S., Petillo, D., Wondergem, B., Anema, J., Kahnoski, R., Teh, B., Stratton, M., & Futreal, P. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes Nature, 463 (7279), 360-363 DOI: 10.1038/nature08672
  • Niu X, Zhang T, Liao L, Zhou L, Lindner DJ, Zhou M, Rini B, Yan Q, Yang H (2011). The von Hippel-Lindau tumor suppressor protein regulates gene expression and tumor growth through histone demethylase JARID1C. Oncogene. Jul 4. DOI: 10.1038/onc.2011.266.
  • Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, Harper KT, Brinkhuizen T, Menko FH, Davies DM, Land SC, Pause A, Baar K, van Steensel MA, & Tee AR (2011). Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene, 30 (10), 1159-73 PMID: 21057536

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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