Department of Pharmacology and Chemical Biology

Posttranslational modifications in mitotic regulation and cancer treatment


Control of G2/M transition and mitotic progression during the cell cycle is crucial for DNA damage checkpoint response and maintenance of chromosomal stability. Defects in either G2/M checkpoint or maintenance of chromosomal integrity often results in malignant cellular transformation. Development of cancer therapies through sensitizing G2/M transition or inducing mitotic catastrophe has became an attractive strategy for anti-cancer therapies. We recently identified two new players (ARID1A and USPx) that govern G2/M transition and chromosomal stability. While current deep sequencing analyses have revealed  a clinical connection  between  genetic  mutations  on ARID1A with ovarian and breast cancers, our pathological studies have demonstrated a tight association between aberrant expression

of USPx with breast cancer. We have recently found that both ARID1A and USPx are regulated by phosphorylation, ubiquitylation and sumoylation during cell cycle and identified such regulators upstream of ARID1A or USPx. We are currently studying the molecular mechanism by which ARID1A or USPx is regulated during transition from G2 to mitosis as well as during chromatid segregation and cytokinesis and how impaired regulation of ARID1A or USPx would impact breast carcinogenesis by using a breast cancer animal model. In addition, we are now developing chemical modulators of ARID1A or USPx that could sensitize cells to Taxol and other anti-mitotic drugs as part of a breast cancer treatment.