Deleted in liver cancer-1 (DLC-1) has been recognized as a major tumor suppressor gene (TSG) and is increasingly considered as a metastasis suppressor gene (MSG) in multiple cancers. Over the past few years our work focused primarily in protein interaction, a new area of our research program designed to gain insights into the function of Deleted in liver cancer-1 gene. A yeast-two hybrid screening identified several binding partners of Deleted in liver cancer-1 that were confirmed in human cells and thus enabling us to examine the consequences of their interactions on Deleted in liver cancer-1 function. Our previous studies underlined the importance to Deleted in liver cancer-1 interaction with proteins other than Rho GTP ases and their therapeutic implication. In the last year a novel protein interacting with Deleted in liver cancer-1 was identified, potential therapeutic applications related to DLC1 antitumor effects combined with tumor promoting action of MYC oncogene in human hepatocellular carcinoma (HCC) have been proposed and a preclinical evaluation showing that the robust antitumor effect of a potent histone deacetylase (HDAC) inhibitor and restoration of Deleted in liver cancer-1 expression in prostate cancer cells may be therapeutically beneficial in this form of cancer. Deleted in liver cancer-1 protein interaction with alpha-catenin was demonstrated, the binding motifs of both proteins were identified and by immunofluorescence staining the two binding partners were colocalized together with adherens junctions (AJs). DLC-1-alpha-catenin complex reduced Rho GTP level at plasma membrane, increased E-cadherin expression that resulted in disruption of cytoskeleton organization and stabilization of AJs. Functional relevance was assessed by knocking down alpha-catenin in DLC-1-positive cells, an experiment that had multiple effects underlining an important role for Deleted in liver cancer-1 in AJs. This interaction is highly relevant to the metastatic process as the observed functions resulted in a strong oncosuppressive effect of DLC1 on metastatic prostate carcinoma cells. Inactivation of TSGs is a major contributing alteration in the initiation or progression of cancer. Down regulation and inactivation of Deleted in liver cancer-1 is mediated predominantly by promoter hypermethylation and histone deacetylation. Because DNA methyltransferase and HDAC inhibitors can induce the restoration of Deleted in liver cancer-1 expression, the Deleted in liver cancer-1 protein may also represent a potential target for novel therapies. Given the considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly HDAC inhibitors, have been developed and used successfully in clinical trials. Both Deleted in liver cancer-1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in prostate cancer cells. This combination regimen almost completely inhibited the tumors growth in nude mice thus validating this protocol as a potentially new therapeutic option in prostate cancer. Despite heterogeneity of genomic alterations in Hepatocellular Carcinoma, certain chromosomes or chromosomal sites are more commonly deleted or amplified, which results in deregulation of critical genes that, ultimately, may trigger malignant transformation of normal hepatocytes. Among the best example is the pattern of genomic alterations of chromosome 8 in Hepatocellular Carcinoma. This chromosome elicits recurrent of DNA copy number loss on the short arm (8p21) and gain on the long arm (8q34). These sites carry the loci of the Deleted in liver cancer-1 (TSG) and MYC oncogene. Overwhelming evidence accumulated in recent years demonstrates that DLC1 and MYC gene are involved pathogenesis of murine and human Hepatocellular Carcinoma. The opposite effects DLC1 and MYC in initiation and progression of Hepatocellular Carcinoma suggests that therapeutics simultaneously targeting signaling pathways governing the functions of both genes could be beneficial in the treatment of Hepatocellular Carcinoma. The inhibition of RhoA pathway and Rho kinase, a downstream effector of Rho, tops the options for therapeutic interventions. Currently, a major effort is underway to develop small molecule Rho kinase inhibitors to treat various disorders, including Hepatocellular Carcinoma. On the other hand, future pharmacologic interventions targeting MYC should be guided by a new strategy that takes into account the differential MYC roles of either tumor promoting or tumor suppressing, depending on its level of expression, and also should consider modulation of the two opposite functions of MYC oncoprotein. However, quarfloxin CX-3453, which targets MYC expression through a four-stranded DNA structure that reached clinical trials for other cancers, has the potential to be effective in therapy for liver cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010038-17
Application #
8552645
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
2012
Total Cost
$1,234,398
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zhou, Xiaoling; Yang, Xu-Yu; Popescu, Nicholas C (2012) Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells. Biochem Biophys Res Commun 420:325-30
Yang, Xuyu; Popescu, Nicholas C; Zimonjic, Drazen B (2011) DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism. Cancer Res 71:2916-25
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Zhou, Xiaoling; Yang, Xu-Yu; Popescu, Nicholas C (2010) Synergistic antineoplastic effect of DLC1 tumor suppressor protein and histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), on prostate and liver cancer cells: perspectives for therapeutics. Int J Oncol 36:999-1005
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Ullmannova-Benson, V; Guan, M; Zhou, X et al. (2009) DLC1 tumor suppressor gene inhibits migration and invasion of multiple myeloma cells through RhoA GTPase pathway. Leukemia 23:383-90
Zimonjic, Drazen B; Ullmannova-Benson, Veronika; Factor, Valentina M et al. (2009) Recurrent and nonrandom DNA copy number and chromosome alterations in Myc transgenic mouse model for hepatocellular carcinogenesis: implications for human disease. Cancer Genet Cytogenet 191:17-26
Yang, X-Y; Guan, M; Vigil, D et al. (2009) p120Ras-GAP binds the DLC1 Rho-GAP tumor suppressor protein and inhibits its RhoA GTPase and growth-suppressing activities. Oncogene 28:1401-9