Breakthrough Research Areas

Cancer disproportionately affects the male sex across racial, geographic and socioeconomic spectra; this is exemplified in bladder cancer in which more than 75% of patients are males. Many attributed this male bias to extrinsic factors such as environmental hazards and tobacco smoking, however, studies have shown that intrinsic biological factors such as sex hormones and sex chromosomes must also be playing a role.

Historically, the study of sex as a biological variable (SABV) overly emphasized gonadal sex. After decades of research, it is now more common to include the discussion of the chromosomal (genetic) sex in the study of SABV. At the Li Lab, we contributed to expanding this framework by verifying and defining the role of the chromosomal sex as well as other major sex-biasing factors, including epigenetic regulators and immune cells. Using a sex-reversed mouse model, we showed that sex chromosomes modulate bladder cancer risk independent of sex hormones. We also found that in bladder cancer, the hazard ratio of gonadal hormone effects (GHE) and sex chromosome effects (SCE) equaled the product rather than sum of its individual hazard ratio, suggesting synergy between the two. Overall, we expanded the study of SABV to include new sex-biasing agents; we also introduced the phenomenon that sex-biasing factors can have both independent and interactive functions. Only an accurate consideration of both independent and cross-talk effects between major sex-biasing factors can yield sustainable and effective clinical change for patients. To ensure this, we are proactively collaborating with labs at Cedars-Sinai and outside of Cedars-Sinai that specialize in expertise outside of our own to account for the whole picture of SABV.

In 2018, we identified the first prototypical female-biased epigenetic regulator—lysine demethylase 6A (KDM6A)—suppressing bladder tumorigenesis. Our study found that urothelium-specific deletion of KDM6A reduced the baseline male-to-female bladder cancer risk ratio by more than fivefold, suggesting its function as a female-biased tumor suppressor. KDM6A conditional knockouts in males did not show worse survival, indicating that a paralog of KDM6A on the Y chromosome may be compensating loss of function KDM6A mutations on the X chromosome. KDM6A is an interesting gene for multiple reasons: (1) it is commonly mutated in bladder cancer, (2) it promotes expression of canonical Tp53 gene targets, (3) it is prone to escape X chromosome inactivation, resulting in an extra functional copy in females, and (4) it is a major epigenetic regulator. Based on our findings, we are pioneering the novel concept that the epigenetic sex or sex epigenome—the collective set of male and female sex-specific epigenetics—modulates bladder cancer risk and pathogenesis. Sex hormone and sex chromosome effects may alter the sex epigenome to render its sex-biasing effects. Characterizing the sex epigenome has many implications both in producing new lines of therapeutics for bladder cancer and in understanding the epigenetic basis of sex differences in diseases beyond bladder cancer.