Oral Presentation ASPCR-ASDR Conference 2013

Brm is a tumour suppressor gene that protects from UV-induced skin and ocular cancer (#76)

Gary M. Halliday 1 , Paul W. Sou 1 , Nur Mohammad M. Hassan 1 , Richard A. Scolyer 2 , Nick Di Girolamo 3 , Guy Lyons 1
  1. Dermatology Bosch Institute, Royal Prince Alfred Hospital and University of Sydney, Sydney, NSW, Australia
  2. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  3. School of Medical Sciences, University of NSW, Sydney, NSW, Australia

SWI/SNF unravels DNA from its tightly compacted chromatin structure to make it accessible for processes such as transcription and DNA repair. The energy for this process derives from ATP and all SWI/SNF complexes contain one of two mutually exclusive ATPase subunits, Brm or Brg-1. Brm, like other subunits of SWI/SNF is therefore a master regulator of multiple cellular processes. We identified a novel hotspot mutation in Brm in human skin cancer, and also found that both Brm and Brg-1 protein have low expression in human skin cancers. Mice were exposed to a low dose ultraviolet (UV) irradiation protocol that caused few skin tumours in wild-type mice. Brm-/- mice with both p53 alleles intact had an increased incidence of skin and ocular tumours compared to Brm+/+p53+/+ controls. Brm loss in p53+/- mice did not further enhance skin or ocular cancer incidence beyond the increased photocarcinogenesis in p53+/- mice. However, the skin tumours that arose early in Brm-/-p53+/- mice had a higher growth rate. Unexpectedly, Brm-/- inhibited UV-induced immunosuppression, which would be predicted to reduce rather than enhance photocarcinogenesis. In conclusion, the absence of Brm increased skin and ocular photocarcinogenesis. Even when one allele of p53 is lost, Brm has additional tumour suppressing capability. As the Brm gene is mutated in human skin cancer and protein expression is reduced, and it protects from the damaging effects of UV, it may be important in human skin and ocular carcinogenesis.