Over the past few years, DLC1 gained the status of a major tumor suppressor gene and is increasingly recognized as a metastasis suppressor gene. In the last two years our work focused in protein interaction, a new area of our research program designed to gain insights into the function of DLC1 gene. A yeast two hybrid screening identified several binding partners of DLC1 that were confirmed in human cells and thus enabling us to examine the consequences of their interactions on DLC1 function. Our previous studies underlined the importance to DLC1 interaction with proteins other than Rho GTPases and their therapeutic implication. We characterized a new DLC1 interaction with S100A10 an inflammatory protein and a key cell surface receptor for plasminogen that regulates pericellular proteolysis and tumor cell invasion. DLC1 and Annexin A2 shear the same binding site at the C-terminus of S110A10. DLC1 binding displaced annexin 2 thus making it accessible to ubiquitin dependent degradation that in turn resulted in a dose dependent down regulation of S100A2 expression. This process attenuated plasminogen activation and was accompanied by inhibition of in vitro cell migration, invasion, colony formation, and anchorage independent growth of aggressive lung cancer cells. DLC1 binding to S100A10 did not affect DLC1 RhoGAP activity. Thus, this study unraveled a novel GAP-independent mechanism that contributes to the tumor suppressive activity of DLC1 and most importantly provides a plausible mechanism for DLC1 anti metastatic function through which conversion of plasminogen to plasmin diminish tumor cell capacity for invasion and metastasis in the tumor microenvironment. Currently, DLC1 is considered as a metastasis suppressor gene and its involvement in the process of metastasis through interaction with S100A10 protein provides a valid target for therapeutic intervention in the most harmful event in cancer progression. In the last year annual report we described the isolation and characterization of novel DLC1 isoform 4 (DLC1i4) that is significantly downregulated by promoter methylation in a high number of nasopharyngeal, esophageal, gastric, breast, colorectal, cervical and lung carcinoma cell lines as well as in primary tumors and has potent tumor suppressor activity. Inadvertently, the results shoving a high frequency of deregulation DLC1i4 in liver cancer were omitted. Human liver cancer is of central interest in our laboratory and frequent epigenetic downregulation of the new DLC1 isoform together with similar data generated with another isoform underlined the complexity of DLC1 activity in hepatocarcinogenesis. In a previous collaborative study it has been demonstrated that the introduction of an intact chromosome 16 or of fragments corresponding to 16q22-qter or 16q23-qter into breast cancer cells revealed the presence of a cell senescence gene at region 16q24. This year using a similar approach, a novel senescence gene locus, on chromosome transfer into immortal ovarian tumor cells identified 6 designated SEN6A. To refine the gene locus, intact chromosome 6 or 6q were transferred into rat ovarian tumor cells and a panel of immortal revertant clones of senescent cells was generated. The analysis of these revertant cells indicated the presence of a senescence gene confined to the region 6q16.3. Using a functional assay, it was demonstrated that transfer of a YAC clone that maps at 6q16.3 restores senescence in both rat and human ovarian and breast tumor cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010038-16
Application #
8348954
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2011
Total Cost
$1,078,567
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
Low, J S W; Tao, Q; Ng, K M et al. (2011) A novel isoform of the 8p22 tumor suppressor gene DLC1 suppresses tumor growth and is frequently silenced in multiple common tumors. Oncogene 30:1923-35
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
Drgonova, J; Zimonjic, D B; Hall, F S et al. (2010) Effect of KEPI (Ppp1r14c) deletion on morphine analgesia and tolerance in mice of different genetic backgrounds: when a knockout is near a relevant quantitative trait locus. Neuroscience 165:882-95
Liu, Jinglan; Kaur, Gurpreet; Zhawar, Vikramjit K et al. (2009) Role of SV40 integration site at chromosomal interval 1q21.1 in immortalized CRL2504 cells. Cancer Res 69:7819-25
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
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
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Zimonjic, Drazen B; Zhou, Xiaoling; Lee, Ju-Seog et al. (2009) Acquired genetic and functional alterations associated with transforming growth factor beta type I resistance in Hep3B human hepatocellular carcinoma cell line. J Cell Mol Med 13:3985-92