Key words: Transcriptional regulation, oncogenes, cancer biology, chromatin Research interests
Transcriptional deregulation plays a critical role in the development of many cancers. Mechanisms that result in oncogenic transcriptional deregulation include alterations in the expression or structure of proteins that modulate transcription directly or through epigenetic modifications. Hematopoetic cancers and solid tumors (in particular sarcomas) frequently harbor recurrent and specific cytogenetic abnormalities such as chromosomal translocations and amplifications. In many of these cancers, the pathognomonic translocations involve genes that encode transcription factors. Translocations combine features of both native genes to generate unique fused (or chimeric) genes characterized by alterations in expression and structure. Although the importance of these gene fusions to cancer development has been clearly demonstrated, a fundamental understanding of how these changes mediate oncogenesis remains elusive.
Notable examples of translocation-associated transcription factor dysregulation include the MYC or MiT basic helix-loop-helix leucine zipper families which can be amplified or translocated in a wide range of cancers including lymphoma, neuroblastoma, melanoma, pediatric renal carcinoma and clear cell sarcoma. Similarly, ETS winged helix-turn-helix transcription factors and PAX3 or PAX7 paired box/homeodomain transcription factors are translocated in Ewing’s sarcoma and alveolar rhabdomyosarcoma, respectively. In each case, the abnormal transcription factor plays central role in the oncogenic process.
While it is presumed that these deregulated transcription factors mediate oncogenesis by altering target gene expression, we lack a mechanistic understanding of how dysregulation modifies the activity of these transcription factors and their participation in transcriptional networks. Furthermore, in contrast to the success of chimeric kinase inhibition, the molecular attributes of transcription factors make them challenging candidates for therapeutic modulation by small molecules. Focusing on those classes of transcription factors strongly implicated in oncogenesis, our lab employs genomic and proteomic approaches to study transcription factor targeting and gene regulation in cancer and in normal development. Through the identification of oncogenic transcriptional mechanisms and relevant transcriptional targets, we hope to develop novel biologically based therapies for these cancers.