Histone Modification and Glioblastoma Multiforme Therapy
Findings by researchers in the Mayo Clinic Brain Cancer SPORE led them to hypothesize that histone methyltransferase (HMT) MMSET is a contributor to chemoresistance and radioresistance in patients with glioblastoma multiforme. MMSET (also called WHSC1, NSD2) has been shown to methylate histone H4 Lys20 (H4K20), H3 Lys27 (H3K27) and H3 Lys36 (H3K36).
Aside from several reports linking MMSET to transcriptional regulation, its cellular function remains obscure.
The Mayo Clinic Brain Cancer SPORE project team found that MMSET participates in the ATM-MDC1-53BP1 pathway during the DNA damage response. Specifically, MMSET accumulates at sites of DNA damage.
Correlating with this, H4K20 methylation, which is required for 53BP1 recruitment, also increases at DNA damage sites. Downregulation of MMSET decreases H4K20 methylation and abolishes the accumulation of 53BP1 to DNA damage sites.
These results suggest that MMSET functions as an upstream regulator of 53BP1 through its HMT activity. In support of its role in DNA damage responses, MMSET affects cellular sensitivity to temozolomide and radiation.
The Brain Cancer SPORE team also found that MMSET is overexpressed in a subset of glioblastoma lines and that overexpression of MMSET is associated with resistance to temozolomide and radiation.
Based on these preliminary findings, the research team hypothesizes that MMSET regulates 53BP1 and the temozolomide and radiation response, and that misregulation of MMSET could affect glioblastoma multiforme sensitivity to chemoradiotherapy.
This project has three aims.
Aim 1: Structure-function analysis of MMSET in the DNA damage response
The Brain Cancer SPORE is researching structure-function analysis of MMSET in the DNA damage response.
The project team found that MMSET regulates cellular response to temozolomide and radiation. In addition, MMSET regulates histone H4K20 methylation and the recruitment of 53BP1 to the sites of DNA damage.
However, it's not clear if 53BP1 is the major downstream factor of MMSET in DNA damage response. MMSET could also regulate other DNA damage factors through its methyltransferase activity or protein-protein interactions. In addition, MMSET could modulate DNA damage response through its transcriptional activity.
The research team is investigating these potential mechanisms.
Aim 2: Role of MMSET in TMZ/RT response
The Brain Cancer SPORE is investigating the role of MMSET in TMZ/RT response using mouse models.
The project team is using primary xenograft models to examine the influence of MMSET overexpression on temozolomide and radiation resistance.
The team is also exploring ways to sensitize glioblastoma multiforme that have MMSET overexpression to temozolomide and radiation treatment.
Aim 3: MMSET expression in glioblastoma multiforme
This brain cancer research project is examining the expression of MMSET in patients with glioblastoma multiforme and its correlation with temozolomide and radiation response.
The project team is using clinical samples to examine the influence of MMSET overexpression on temozolomide and radiation resistance in relationship to another key prognostic marker, MGMT promoter methylation.
This project is also testing whether overexpression of MMSET contributes to the chemoradioresistance of glioblastoma multiforme. This research could ultimately lead to the identification of a novel drug target and biomarker for glioblastoma multiforme therapy.
Co-leaders of this Brain Cancer SPORE project are: