Research

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. Exploring molecular contributors to HNSCC, we identified LZAP as a tumor suppressor with activity inhibit NF-KB by dephosphorylation of RelA and activate p53. Mechanisms through which LZAP performs these activities are not well understood, but our studies suggest that LZAP inhibits tumor formation by inactivation of NF-kB while simultaneously activating p53. Loss of LZAP protects wild-type p53 cells but sensitizes p53 mutant or null cells to radiation or chemotherapy. Thus, temporary inhibition of LZAP activity may be beneficial for avoiding toxic side effects of anticancer therapies by sensitizing tumors while protecting normal surrounding tissues.

NF-kB transcriptional activity is regulated by phosphorylation of RelA and while kinases responsible for phosphorylation and activation are described much less is known about dephosphorylation and inhibition of RelA. We identified that a phosphatase, PPM1A has tumor suppressor-like activity at least partially due to dephosphorylation of RelA. We are now exploring how LZAP regulates PPM1A and its family members and restoration of PPM1A activity as a means to inactivated RelA and prevent metastases.

In addition to exploring LZAP activities using standard molecular techniques, we created a mouse model of LZAP loss. Because homozygous loss of LZAP results in embryonically lethality, spontaneous tumorigenesis was evaluated and found to be increased in heterozygous (LZAP+/-) mice. We are now exploring carcinogen- and oncogene-induced murine models. These studies are designed to determine the relative contribution of LZAP regulation of p53 and/or NF-kB to LZAP tumor suppressor activities