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Jonathan R Pollack - One of the best experts on this subject based on the ideXlab platform.

  • the retinoic acid synthesis gene ALDH1A2 is a candidate tumor suppressor in prostate cancer
    Cancer Research, 2005
    Co-Authors: Hanna Kim, David E. Ong, Jacques Lapointe, James D Brooks, Gulsah Kaygusuz, Matt Van De Rijn, Jonathan R Pollack
    Abstract:

    Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), was also associated with shorter recurrence-free survival. ALDH1A2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1A2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1A2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1A2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1A2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer.

  • ALDH1A2 is a candidate tumor suppressor gene in prostate cancer
    Cancer Research, 2005
    Co-Authors: Hanna Y Kim, Jacques Lapointe, James D Brooks, Jonathan R Pollack
    Abstract:

    1835 Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-aza-dC. Of the 356 genes that were induced by 5-Aza-dC treatment, 49 also displayed reduced expression in primary prostate tumors compared to normal prostate tissue, and the decreased expression of only one gene, ALDH1A2 (Aldehyde dehydrogenase 1 family, member A2), was associated with reduced tumor-free survival. ALDH1A2 encodes an enzyme responsible for synthesis of retinoic acid, a compound with pro-differentiation properties. By immunohistochemistry, we observed that ALDH1A2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1A2 promotor region was significantly hypermethylated in prostate cancer compared to normal prostate specimens (P=0.024). Finally, transfection-mediated re-expression of ALDH1A2 in the prostate cancer cell line DU145 resulted in decreased colony growth (P

Makoto Iwata - One of the best experts on this subject based on the ideXlab platform.

  • retinoic acid and gm csf coordinately induce retinal dehydrogenase 2 raldh2 expression through cooperation between the rar rxr complex and sp1 in dendritic cells
    PLOS ONE, 2014
    Co-Authors: Yoshiharu Ohoka, Naoko Maeda, Hajime Takeuchi, Aya Yokotanakatsuma, Makoto Iwata
    Abstract:

    Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by ALDH1A2 is a key enzyme for generating RA in DCs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to ALDH1A2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced ALDH1A2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow-derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and ALDH1A2 expression. Sp1 and the RARα/RXRα complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse ALDH1A2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARα/RXRα and Sp1 synergistically enhanced ALDH1A2 promoter-reporter activity. GM-CSF did not significantly induce ALDH1A2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the ALDH1A2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the ALDH1A2 promoter, and can be regulated by a DNA methylation-independent mechanism.

Yoshiharu Ohoka - One of the best experts on this subject based on the ideXlab platform.

  • retinoic acid and gm csf coordinately induce retinal dehydrogenase 2 raldh2 expression through cooperation between the rar rxr complex and sp1 in dendritic cells
    PLOS ONE, 2014
    Co-Authors: Yoshiharu Ohoka, Naoko Maeda, Hajime Takeuchi, Aya Yokotanakatsuma, Makoto Iwata
    Abstract:

    Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by ALDH1A2 is a key enzyme for generating RA in DCs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to ALDH1A2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced ALDH1A2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow-derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and ALDH1A2 expression. Sp1 and the RARα/RXRα complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse ALDH1A2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARα/RXRα and Sp1 synergistically enhanced ALDH1A2 promoter-reporter activity. GM-CSF did not significantly induce ALDH1A2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the ALDH1A2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the ALDH1A2 promoter, and can be regulated by a DNA methylation-independent mechanism.

Jae Hoon Kim - One of the best experts on this subject based on the ideXlab platform.

  • ALDH1A2 is a candidate tumor suppressor gene in ovarian cancer
    Cancers, 2019
    Co-Authors: Jung A Choi, Hyunja Kwon, Hanbyoul Cho, Joonyong Chung, Stephen M Hewitt, Jae Hoon Kim
    Abstract:

    Aldehyde dehydrogenase 1 family member A2 (ALDH1A2) is a rate-limiting enzyme involved in cellular retinoic acid synthesis. However, its functional role in ovarian cancer remains elusive. Here, we found that ALDH1A2 was the most prominently downregulated gene among ALDH family members in ovarian cancer cells, according to complementary DNA microarray data. Low ALDH1A2 expression was associated with unfavorable prognosis and shorter disease-free and overall survival for ovarian cancer patients. Notably, hypermethylation of ALDH1A2 was significantly higher in ovarian cancer cell lines when compared to that in immortalized human ovarian surface epithelial cell lines. ALDH1A2 expression was restored in various ovarian cancer cell lines after treatment with the DNA methylation inhibitor 5-aza-2′-deoxycytidine. Furthermore, silencing DNA methyltransferase 1 (DNMT1) or 3B (DNMT3B) restored ALDH1A2 expression in ovarian cancer cell lines. Functional studies revealed that forced ALDH1A2 expression significantly impaired the proliferation of ovarian cancer cells and their invasive activity. To the best of our knowledge, this is the first study to show that ALDH1A2 expression is regulated by the epigenetic regulation of DNMTs, and subsequently that it might act as a tumor suppressor in ovarian cancer, further suggesting that enhancing ALDH1A2-linked signaling might provide new opportunities for therapeutic intervention in ovarian cancer.

Jacques Lapointe - One of the best experts on this subject based on the ideXlab platform.

  • the retinoic acid synthesis gene ALDH1A2 is a candidate tumor suppressor in prostate cancer
    Cancer Research, 2005
    Co-Authors: Hanna Kim, David E. Ong, Jacques Lapointe, James D Brooks, Gulsah Kaygusuz, Matt Van De Rijn, Jonathan R Pollack
    Abstract:

    Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-dC). Of the 271 genes that were induced by 5-aza-dC treatment, 25 also displayed reduced expression in primary prostate tumors compared with normal prostate tissue, and the decreased expression of only one gene, aldehyde dehydrogenase 1 family, member A2 (ALDH1A2), was also associated with shorter recurrence-free survival. ALDH1A2 encodes an enzyme responsible for synthesis of retinoic acid (RA), a compound with prodifferentiation properties. By immunohistochemistry, we observed that ALDH1A2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1A2 promoter region was significantly hypermethylated in primary prostate tumors compared with normal prostate specimens (P = 0.01). Finally, transfection-mediated reexpression of wild-type ALDH1A2 (but not a presumptive catalytically dead mutant) in the prostate cancer cell line DU145 resulted in decreased colony growth (P < 0.0001), comparable with treatment with either 5-aza-dC or RA. Taken together, our findings implicate ALDH1A2 as a candidate tumor suppressor gene in prostate cancer and further support a role of retinoids in the prevention or treatment of prostate cancer.

  • ALDH1A2 is a candidate tumor suppressor gene in prostate cancer
    Cancer Research, 2005
    Co-Authors: Hanna Y Kim, Jacques Lapointe, James D Brooks, Jonathan R Pollack
    Abstract:

    1835 Prostate cancer is the most common cancer among men in the United States, and aberrant DNA methylation is known to be an early molecular event in its development. Here, we have used expression profiling to identify novel hypermethylated genes whose expression is induced by treatment of prostate cancer cell lines with the DNA methyltransferase inhibitor 5-aza-dC. Of the 356 genes that were induced by 5-Aza-dC treatment, 49 also displayed reduced expression in primary prostate tumors compared to normal prostate tissue, and the decreased expression of only one gene, ALDH1A2 (Aldehyde dehydrogenase 1 family, member A2), was associated with reduced tumor-free survival. ALDH1A2 encodes an enzyme responsible for synthesis of retinoic acid, a compound with pro-differentiation properties. By immunohistochemistry, we observed that ALDH1A2 was expressed in epithelia from normal prostate but not prostate cancer. Using bisulfite sequencing, we determined that the ALDH1A2 promotor region was significantly hypermethylated in prostate cancer compared to normal prostate specimens (P=0.024). Finally, transfection-mediated re-expression of ALDH1A2 in the prostate cancer cell line DU145 resulted in decreased colony growth (P