MISSION

FAMRI Supported Publications
Gibbs A, Schwartzman J, Deng V, Bagby G, Alumkal J. Sulforaphane destabilizes the androgen receptor
and attenuates androgen receptor signaling in prostate cancer cells through inhibition of HDAC6.
Presented at the 15th Annual Prostate Cancer Foundation Meeting. Incline Village, NV, Oct 15-18,
2008.
NDRG1 MODULATION TO DECREASE PROSTATE CANCER INVASION
Sushant K. Kachhap, PhD; The Johns Hopkins University; YCSA 2007
Increased tobacco smoke exposure positively correlates with an increased risk of metastasis, leading to a
poor prognosis in a wide variety of cancers including those of lung, breast, and prostate cancer (PCa).
Downregulation of the E-cadherin adhesion molecule is a common feature of a variety of metastatic
epithelial tumors related to SHS. The N-myc downregulated gene 1 (NDRG1) is a known PCa metastasis
suppressor gene. Apart from an alpha beta hydrolase motif the functionality of which remains questionable,
NDRG1 lacks any known protein motif that can impart it a function. Dr. Kachhap and colleagues have
recently elucidated the function of NDRG1 as a Rab4a effector protein that localizes to the trans Golgi
network where it is involved with recycling of the E-cadherin molecule. Induction of NDRG1 leads to differentiation
of PCa cells and decreases metastasis. Thus, it is hypothesized that the ability to pharmacologically
control the expression of NDRG1 in PCa can potentially reduce invasion/metastasis of PCa. Their
goal is to upregulate NDRG1 in PCa cells with small molecule compounds/drugs to decrease PCa invasion.
Data from microarray analysis in PCA cells treated with histone deacetylase inhibitors (HDACi) indicated
that NDRG1 upregulated by generic HDACis. They show that NDRG1 protein is expressed upon
treatment of PCa cells DU-145 and LNCaP with generic HDACi. Using HDAC isotype-selective
inhibitors supplied by MethylGene Inc., they further evaluated various histone deacetylases (HDACs) that
regulate NDRG1 in these PCa cells. They found that NDRG1 is regulated specifically by an HDAC 1 and
2 selective inhibitor and an HDAC 6 selective inhibitor, but not by an HDAC 8 selective inhibitor. By
using small hairpin RNA for HDAC 1, HDAC 2, HDAC 4, HDAC 6, and HDAC 8 they have further
confirmed that NDRG1 is specifically regulated by HDAC 1 and HDAC 6, and not other HDACs. They
envisage NDRG1 as a pharmacologically anti-metastatic target that can be regulated for PCa. Knowledge
pertinent to the role of specific HDAC isozymes regulating NDRG1 expression will help the rational
development of such therapeutics, thereby decreasing PCa metastasis.
FAMRI Supported Publications
Kortenhorst MS, Zahurak M, Shabbeer S, Kachhap S, Galloway N, Parmigiani G, Verheul HM, Carducci
MA. A multiple-loop, double-cube microarray design applied to prostate cancer cell lines with variable
sensitivity to histone deacetylase inhibitors. Clin Cancer Res 2008;14:6886-6894.
Shabbeer S, Sobolewski M, Anchoori RK, Kachhap S, Davidson N, Carducci MA, Khan SR. Fenugreek: a
naturally occurring edible spice as an anticancer agent. Cancer Biol Ther 2009;8 [Epub ahead of print].
CANCER, THYROID
COMPLETED RESEARCH
BRAF MUTATION AND OTHER COMMON GENETIC AND EPIGENETIC ALTERATIONS IN THYROID CANCER: RELA-
TIONSHIP WITH SMOKING AND CLINICAL APPLICATIONS
Michael M. Xing, MD, PhD; The Johns Hopkins University; CIA 2003
The most common genetic and epigenetic alterations in thyroid cancer involve BRAF (Ras-regulated
kinase) and Ras mutations and aberrant gene methylation. Smoking is linked with Ras mutation in other
cancers, nodular goiter, and Grave’s disease. Both nodular goiter and Grave’s disease are associated with an
increased risk of thyroid cancer. Dr. Xing and collaborators hypothesized that smoking may cause a higher
incidence of certain genetic and epigenetic alterations, such as BRAF and Ras mutations and gene methylation
in thyroid cancer leading to adverse pathological and clinical consequences. Aims of the study
included 1) determining whether smoking causes a specific genetic/epigenetic alterations in thyroid cancer,
such as BRAF and Ras mutations and gene methylation with predilection to a particular subtype and specific
clinicopathological characters; and 2) applying genetic/epigenetic information to thyroid cancer diagnostic
and prognostic evaluation.
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