Gene Regulation/Transcription

Promotes collaborative studies investigating fundamental mechanisms by which gene activity is modulated in normal and neoplastic cells.

Investigator: John Copland, Ph.D.

In the Copland Laboratory, using patient derived normal and tumor tissues, the researchers have performed whole genome wide expression analysis to identify genes aberrantly regulated in human cancers. They have focused upon kidney cancer (renal cell carcinoma) and thyroid cancer, identifying numerous aberrant signaling pathways upregulated or lost in these two cancers. Some of the aberrant signaling pathways discovered and/or elucidated in the laboratory include TGFβ, Wnt/sFRP1, HIF, PPARγ.

Using human cell lines (some of which Dr. Copland's team established from patient-matched normal and tumor tissues), identified genes are silenced or re-expressed establishing transgenic cell lines to determine the role of the gene in tumor survival, proliferation, invasion and metastasis. Identification of aberrant signaling pathways will allow for an understanding of the molecular pathways governing each cancer subtype.

Utilizing this information provides a rational approach in designing combinatorial molecular targeted therapies and will lead to personalized medicine for diagnosis and treatment. The investigators' overarching goal is to understand molecular mechanisms of carcinogenesis and tumor progression. In understanding these molecular mechanisms, they hope to eventually find effective cancer therapies using combinatorial targeted molecular therapies.

Investigator: Norman Eberhardt, Ph.D.

Somatic chromosomal rearrangements involving the PAX8 and PPARγ genes occur frequently in follicular thyroid carcinomas. Studies from Dr. Eberhardt's laboratory have demonstrated that the resulting PAX8/PPARγ fusion gene is an oncogene, which acts partly by inhibiting wild-type PPARγ activity. Currently, they are developing a mouse model of follicular thyroid carcinomas that is based on over-expression of the PAX8/PPARγ fusion gene in thyroid cells.

Additional studies are being directed toward the mechanism of this inhibition and studying the ability PPARγ agonists/antagonists to interfere with the oncogene's function. A major effort of these studies is to identify targets that might lead to new treatments for follicular thyroid carcinomas.

Other studies have focused on anaplastic thyroid cancer one of the most aggressive cancers known with a post-diagnosis life expectancy of less than six months. There are no effective therapies for the treatment of anaplastic thyroid cancer. The laboratory is currently focusing on oncolytic viral approaches toward the treatment of these cancers. Oncolytic viruses are very effective at killing anaplastic thyroid cancer cell lines in vitro and studies in animals are currently underway to ascertain their effectiveness in vivo.

Investigator: E. Aubrey Thompson, Ph.D.

In the Thompson Laboratory, investigators have recently completed a major genomic analysis of PPARγ target genes in early stage colon cancer cells. They developed and utilized a variation of the Baysian statistical machine learning to identify cohorts of PPARγ target genes that regulate metabolism, proliferation, signal transduction, and migration. These data complement parallel analyses of PPARγ function in non-transformed intestinal epithelial cells in vitro and in isolated colonic epithelial cells in vivo.

The results of the genomic analyses generally reflected the cellular phenotype that the team observed upon activation of PPARγ by thiazolidinedione ligands. However, the power of genomic analysis lies in the ability to infer novel regulatory connections that are not intuitively obvious. Two such pathways have been identified. One of these involves activation of the Rho family GTPase Cdc42, which stimulates motility of non-transformed intestinal epithelial cells. Crosstalk between nuclear receptors such as PPARγ and Rho family GTPases had not previously been observed, and prior to publication of Mayo's data, the role of nuclear receptors in cellular motility had not been well established.

A second unexpected pathway that Dr. Thompson's team has identified involves the tumor suppressor Down Syndrome Critical Region 1, originally named DSCR1 but recently renamed Regulator of Calcineurin 1 (RCAN1). DSCR1/RCAN1, as the name implies, is an endogenous calcineurin inhibitor. Induction of RCAN1 by PPARγ results in inhibition of calcineurin, suppression of NFATc transcriptional activity, and inhibition of both cell proliferation and invasion. Intriguingly, RCAN1 induction by PPARγ involves activation of NFATc, and induction of RCAN1 therefore represents a negative feedback loop that constrains NFATc activity in early stage colon cancer cells.

Investigator: Donald Tindall, Ph.D.

The Tindall Laboratory team is studying prostate cancer and the mechanisms by which prostate cancer cells survive following androgen ablation, the most common therapy for advanced prostate cancer. A central component to their work is based upon the hypothesis that the androgen receptor plays a key role in androgen-independent prostate cancer following androgen ablation therapy. To address this issue they are studying the mechanisms by which co-regulatory proteins modulate the transcriptional activity of the androgen receptor and how these proteins are altered in prostate cancer (Cancer Research. 67:3422-30, 2007).

They are also studying the downstream targets of the androgen receptor that are involved in cell proliferation and cell death focusing on the molecular mechanisms by which Forkhead transcription factors affect proliferation and apoptosis in prostate cancer cells (Cell Cycle. 6:902-6, 2007). The researchers believe that this research will identify cellular targets for detection, prognosis, prevention and treatment of prostate cancer.

Investigator: Zhiguo Zhang, Ph.D.

Dr. Zhang's Laboratory is studying how the inheritable repression of gene expression within chromatin domains (i.e., epigenetic silencing) is achieved through formation of a chromatin state called heterochromatin. Inappropriate gain of heterochromatic structures, such as silencing of tumor suppressor genes, plays a causal role in carcinogenesis of many forms of cancer. To that end, Dr. Zhang was awarded a five-year RO1 grant from the National Cancer Institute to study the function of CAF-1 (a protein complex which plays a key role in chromatin assembly after DNA replication) in epigenetic inheritance as well as a developmental award from Mayo Clinic Cancer Center's Brain SPORE to investigate histone modifications as prognostic markers for gliomas.

More recently his laboratory discovered a novel class of histone acetyltransferase Rtt109 that acetylates lysine 56 of histone H3 and functions to maintain genome stability during normal S phase of the cell cycle as well as under stress caused by DNA damage agents (Science. 315 (5812): 653-655, 2007).