Bladder Cancer Gender & Sex Program
Epigenetics
Methylation and acetylation of genes and histones (and the removal of these methyl and aceytyl groups) are epigenetic modifications that inhibit or promote certain genes—showcasing the ingenious ways cells "edit" the working genome.
We believe that males and females have sex-specific epigenetic modifications that we collectively refer to as the "sex epigenome". Defining the sex epigenome can eventually be leveraged in a new line of therapeutics in precision medicine.
As previously mentioned, KDM6A is an important female-biased epigenetic regulator, functioning as a demethylase. Enhancer of zeste homolog 2 (EZH2) antagonizes KDM6A's demethylase activity (1). In a preclinical study, EZH2 inhibitors recovered KDM6A demethylase function and proved therapeutically effective (2). Because KDM6A mutations are more common in women with non-muscle invasive BC (3), we believe that a possible research direction can test whether EZH2 inhibitors can treat female BC patients with KDM6A mutations.
DNA topoisomerase 2 beta (TOP2B), another epigenetic regulator, exhibited male-biased DNA methylation in BC patients (4). Valrubicin—an analog of doxorubicin used for BCG refractory patients—antagonizes topoisomerase activity but it has not yet been tested whether males and females respond differently to Valrubicin.
Collectively, there is evidence that males and females have sex-specific epigenetic regulators. A systematic characterization of the sex epigenome could lead to improved sex-based precision medicine for BC patients and this is what we aim to discover at the BCGSP.
References:
1) Guo C, Balsara ZR, Hill WG, Li X. Stage- and subunit-specific functions of polycomb repressive complex 2 in bladder urothelial formation and regeneration. Development. 2017;144(3):400-8.
2) Ler LD, Ghosh S, Chai X, Thike AA, Heng HL, Siew EY, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med. 2017;9(378).
3) Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE, et al. Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. Cancer Cell. 2017;32(5):701-15 e7.
4) Yuan Y, Liu L, Chen H, Wang Y, Xu Y, Mao H, et al. Comprehensive Characterization of Molecular Differences in Cancer between Male and Female Patients. Cancer Cell. 2016;29(5):711-22.