Regulation of HTLV-I oncoprotein Tax by PDLIM2

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Its encoded oncoprotein Tax plays the key roles in HTLV-I-mediated cell transformation and pathogenesis. Although the mechanisms by which the HTLV-I Tax deregulates cellular signaling for oncogenesis have been extensively studied, how Tax itself is regulated remains largely unknown. Here we showed that PDZ-LIM domain-containing protein 2 (PDLIM2, SLIM or Mystique) negatively regulated Tax by promoting poly-ubiquitination and proteasomal degradation of Tax, so that to suppress Tax-mediated signaling activation, cell transformation and oncogenesis both in vitro and in animal. To further define the molecular determinant responsible for PDLIM2 mediated Tax suppression, we characterized that a putative á-helix motif of PDLIM2 at amino acids 236-254 was crucial for the interaction between PDLIM2 and Tax. PDLIM2 with selective disruption of this short helix lost the tumor suppression function and failed in altering Tax subcellular distribution as well as promoting Tax proteasomal degradation. Additionally, the expression of PDLIM2 was down-regulated in HTLV-I-transformed T cells and primary ATL samples, and the re-introduction of PDLIM2 reversed the tumorigenicity of the malignant cells. The evidence indicated that the counterbalance between HTLV-I Tax and PDLIM2 might determine the outcome of HTLV-I infection. Meanwhile, in those HTLV-I-transformed T cells, we found that DNA methyltransferases (DNMT) 1 and 3b but not 3a were over-expressed, suggesting the involvement of DNA methylation in PDLIM2 repression. Consistently, the hypomethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) restored PDLIM2 expression and induced death of these malignant cells. Our studies provided important insights into the function of PDLIM2 in HTLV-I leukemogenicity, long latency and cancer heath disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, our studies also suggest potential therapeutic approaches for ATL, a disease with poor treatments

Human T-Cell Leukemia Virus Type I-Mediated Repression of PDZ-LIM Domain-Containing Protein 2 Involves DNA Methylation But Independent of the Viral Oncoprotein Tax1

Human T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL). Our recent studies have shown that one important mechanism of HTLV-I-Mediated tumorigenesis is through PDZ-LIM domain-containing protein 2 (PDLIM2) repression, although the involved mechanism remains unknown. Here, we further report that HTLV-I-Mediated PDLIM2 repression was a pathophysiological event and the PDLIM2 repression involved DNA methylation. Whereas DNA methyltransferases 1 and 3b but not 3a were upregulated in HTLV-I-transformed T cells, the hypomethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) restored PDLIM2 expression and induced death of these malignant cells. Notably, the PDLIM2 repression was independent of the viral regulatory protein Tax because neither short-term induction nor long-term stable expression of Tax could downregulate PDLIM2 expression. These studies provide important insights into PDLIM2 regulation, HTLV-I leukemogenicity, long latency, and cancer health disparities. Given the efficient antitumor activity with no obvious toxicity of 5-aza-dC, these studies also suggest potential therapeutic strategies for ATL

Bisubstrate-Type Chemical Probes Identify GRP94 as a Potential Target of Cytosine-Containing Adenosine Analogs

International audienceWe synthesized affinity-based chemical probes of cytosine-adenosine bisubstrate analogs and identified several potential targets by proteomic analysis. The validation of the proteomic analysis identified the chemical probe as a specific inhibitor of glucose-regulated protein 94 (GRP94), a potential drug target for several types of cancers. Therefore, as a result of the use of bisubstrate-type chemical probes and a chemical-biology methodology, this work opens the way to the development of a new family of GRP94 inhibitors that could potentially be of therapeutic interest

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2 — resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes — is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (V(max)/K(m)) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30–50% of whom possess the inactive ALDH2*2 mutant allele

Epigenetic Repression of PDZ-LIM Domain-containing Protein 2: IMPLICATIONS FOR THE BIOLOGY AND TREATMENT OF BREAST CANCER*

The NF-κB transcription factor plays a pivotal role in breast cancer progression and therapy resistance. However, the mechanisms by which the tightly regulated NF-κB becomes constitutively activated during breast cancer pathogenesis remain obscure. Here, we report that PDZ-LIM domain-containing protein 2 (PDLIM2), an essential terminator of NF-κB activation, is repressed in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells, suggesting one important mechanism for the constitutive activation of NF-κB. Indeed, PDLIM2 reexpression inhibited constitutive NF-κB activation and expression of NF-κB-targeted genes in those breast cancer cells. Importantly, PDLIM2, but not its mutants defective in NF-κB termination, could suppress in vitro anchorage-independent growth and in vivo tumor formation of those malignant breast cells. In addition, we have shown that PDLIM2 repression involves promoter methylation. Accordingly, treatment of the breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine reverses the methylation of the PDLIM2 promoter, restored PDLIM2 expression, and suppressed tumorigenicities of human breast cancer cells both in vitro and in vivo. These studies thus provide important mechanistic insights into breast cancer pathogenesis. These studies also suggest a tumor suppression function of PDLIM2 and a therapeutic strategy for breast cancer

The tumor suppressor gene WWOX links the canonical and noncanonical NF-κB pathways in HTLV-I Tax-mediated tumorigenesis

Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis