Regulation of type IV collagenase expression

Summary

Principal Investigator: Douglas Boyd
Abstract: The 92 kDa type IV collagenase (MMP-9) contributes to the spread of oral cancer and understanding how its expression is regulated could ultimately yield new agents to repress its expression and diminish tumor invasiveness. Although we previously identified multiple regulatory elements (AP-1, NF-KB, PEA3, Spl) in the 670 base pair promoter, the limited number of these binding sites makes it unlikely that MMP-9 expression is solely the consequence of trans- activation through these motifs. Indeed, emerging studies indicate a role for the chromatin environment (constituted by DNA wrapped around a histone core), in the regulation of gene expression. We show herein that Mtal, which promotes histone deacetylation, represses MMP-9 expression. Further, Mtal expression is undetectable in MMP-9-producing oral cancer. In Specific Aim # 1 using genomic footprinting and ehromatin immunoprecipitation assays (Chip) we will identify transcription factor-bound cis elements and acetylated histones localized at these sites in the 670 base pair MMP-9 promoter targeted by Mtal to achieve MMP-9 repression. Biological suppressors of MMP-9 expression may also provide a tool for identifying regulatory elements in the chromatinized promoter. We show herein that the metastasis suppressor gene KISS-1 attenuates MMP-9 transcription partly by reducing NF-KB binding to the chromatinized promoter. However, the degree to which NF-KB binding is reduced can only partly account for the diminished transcription. Therefore, in Specific Aim # 2, we will identify trans -activated cis elements and acetylated histones localized at these sites in the MMP-9 promoter that mediate KiSS-l-dependent repression of MMP-9. Similarly, the MEK1 inhibitor PD098059 represses MMP-9 expression and in Specific Aim # 3 we will determine if the transcriptional targets of this repressor are identical to, or distinct from, those of Mtal and KiSS-I. If we determine that the transcriptional targets differ, we will determine whether combining PD098059 and KISS-1 or Mtal proves superior to individual modalities in reducing MMP-9 expression and oral cancer invasiveness. Since extra-chromosomal reporters were used in our previous studies of MMP-9 transcription, regulatory elements, that depend on the chromatin environment, may have escaped detection. Thus, to identify such novel cis elements in Specific Aim # 4, we will employ DNaseI hypersensitivity, genomic footprinting and Egtll library screening to identify additional trans- activators/repressors of MMP-9 expression. Ultimately, the goal of these studies is to identify new transcriptional targets in the MMP-9 promoter that allow for therapeutic intervention to repress expression of this collagenase and oral cancer invasiveness.
Funding Period: 1994-02-01 - 2008-05-30
more information: NIH RePORT

Top Publications

  1. ncbi Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin
    Chunhong Yan
    Department of Cancer Biology, University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cancer Ther 4:233-41. 2005
  2. pmc Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin beta 4 and vascular endothelial growth factor as downstream targets
    Lin Yang
    Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 283:35295-304. 2008
  3. ncbi The previously undescribed ZKSCAN3 (ZNF306) is a novel "driver" of colorectal cancer progression
    Lin Yang
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer Res 68:4321-30. 2008
  4. ncbi A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression
    Rajesh R Nair
    Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 73:919-29. 2008
  5. ncbi Regulation of matrix metalloproteinase gene expression
    Chunhong Yan
    MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA
    J Cell Physiol 211:19-26. 2007
  6. ncbi Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression
    H Wang
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 26:2058-70. 2007
  7. pmc Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression
    Chunhong Yan
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Cell Biol 26:6357-71. 2006
  8. ncbi Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression
    Rajesh R Nair
    Department of Cancer Biology, M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 281:26424-36. 2006
  9. pmc Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination
    Chunhong Yan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    EMBO J 24:2425-35. 2005
  10. pmc Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases
    T Ishiguro
    Cancer Biology Department, MD Anderson Cancer Center, Houston, TX 77030, USA
    Br J Cancer 102:774-82. 2010

Scientific Experts

  • Douglas Boyd
  • Chunhong Yan
  • Lin Yang
  • Rajesh R Nair
  • T Ishiguro
  • H Wang
  • S Y Lin
  • H Avila
  • T Nakamura
  • M Yamamoto
  • Li Zhang
  • Bryant G Darnay
  • Angela Sanguino
  • Toshio Kuwai
  • Qiuyu Wu
  • Lee Ellis
  • MICHELLE LENNARTZ
  • Zhengxin Wang
  • Anil Sood
  • Gabriel Lopez-Berestein
  • Stanley R Hamilton
  • Xujun Ma
  • Hector Avila
  • H Allgayer
  • I Asangani
  • Julian Solway

Detail Information

Publications10

  1. ncbi Gene expression profiling identifies activating transcription factor 3 as a novel contributor to the proapoptotic effect of curcumin
    Chunhong Yan
    Department of Cancer Biology, University of Texas, M D Anderson Cancer Center, Houston, TX 77030, USA
    Mol Cancer Ther 4:233-41. 2005
    ..Thus, we have identified several putative, novel molecular targets of curcumin and showed that one, (ATF3) contributes to the proapoptotic effects of this compound...
  2. pmc Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin beta 4 and vascular endothelial growth factor as downstream targets
    Lin Yang
    Department of Cancer Biology, University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 283:35295-304. 2008
    ..We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin beta 4...
  3. ncbi The previously undescribed ZKSCAN3 (ZNF306) is a novel "driver" of colorectal cancer progression
    Lin Yang
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA
    Cancer Res 68:4321-30. 2008
    ..Thus, the hitherto uncharacterized ZKSCAN3 adds to an expanding set of encoded products contributing to the progression of colorectal cancer...
  4. ncbi A novel high-throughput screening system identifies a small molecule repressive for matrix metalloproteinase-9 expression
    Rajesh R Nair
    Center for Cell Biology and Cancer Research, Albany Medical College, 47 New Scotland Ave, Albany, NY 12208, USA
    Mol Pharmacol 73:919-29. 2008
    ....
  5. ncbi Regulation of matrix metalloproteinase gene expression
    Chunhong Yan
    MD Anderson Cancer Center, University of Texas, Houston, Texas 77030, USA
    J Cell Physiol 211:19-26. 2007
    ..Finally, we argue for potential technologies to regulate MMP expression of utility in pathological conditions where these enzymes are aberrantly expressed...
  6. ncbi Identification of an histone H3 acetylated/K4-methylated-bound intragenic enhancer regulatory for urokinase receptor expression
    H Wang
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    Oncogene 26:2058-70. 2007
    ..Thus, we have defined a novel intragenic enhancer in the u-PAR gene required for constitutive and inducible expression...
  7. pmc Histone H3 acetylation and H3 K4 methylation define distinct chromatin regions permissive for transgene expression
    Chunhong Yan
    Department of Cancer Biology, The University of Texas M D Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
    Mol Cell Biol 26:6357-71. 2006
    ..We therefore propose a model in which histone H3 acetylation and H3 K4 methylation localized to discrete sites in the mammalian genome mark distinct chromatin functions that dictate transgene expression or silencing...
  8. ncbi Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression
    Rajesh R Nair
    Department of Cancer Biology, M D Anderson Cancer Center, Houston, Texas 77030, USA
    J Biol Chem 281:26424-36. 2006
    ..Diminished transgelin expression in several cancers may thus partly account for the elevated MMP-9 expression evident in these tumors...
  9. pmc Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination
    Chunhong Yan
    Department of Cancer Biology, MD Anderson Cancer Center, Houston, TX 77030, USA
    EMBO J 24:2425-35. 2005
    ....
  10. pmc Gene trapping identifies chloride channel 4 as a novel inducer of colon cancer cell migration, invasion and metastases
    T Ishiguro
    Cancer Biology Department, MD Anderson Cancer Center, Houston, TX 77030, USA
    Br J Cancer 102:774-82. 2010
    ..To date, there are few reports on gene products contributing to colon cancer progression...