Arsenic Trioxide Promotes Histone H3 Phosphoacetylation at the Chromatin of CASPASE-10 in Acute Promyelocytic Leukemia Cells

Abstract

Arsenic trioxide (As 2 O 3 ) is highly effective for the treatment of acute promyelocytic leukemia, even in patients who are unresponsive to all-trans-retinoic acid therapy. As 2 O 3 is believed to function primarily by promoting apoptosis, but the underlying molecular mechanisms remain largely unknown. In this report, using cDNA arrays, we have examined the changes in gene expression profiles triggered by clinically achievable doses of As 2 O 3 in acute promyelocytic leukemia NB4 cells. CASPASE-10 expression was found to be potently induced by As 2 O 3 . Accordingly, caspase-10 activity also substantially increased in response to As 2 O 3 treatment. A selective inhibitor of caspase-10, Z-AEVD-FMK, effectively blocked caspase-3 activation and significantly attenuated As 2 O 3 -triggered apoptosis. Interestingly, the treatment of NB4 cells with As 2 O 3 markedly increased histone H3 phosphorylation at serine 10, an event that is associated with acetylation of the lysine 14 residue. Chromatin immunoprecipitation assays revealed that As 2 O 3 potently enhances histone H3 phosphoacetylation at the CASPASE-10 locus. These results suggest that the effect of As 2 O 3 on histone H3 phosphoacetylation at the CASPASE-10 gene may play an important role in the induction of apoptosis and thus contribute to its therapeutic effects on acute promyelocytic leukemia.Acute promyelocytic leukemia (APL) 1 accounts for ϳ10 -15% of adult myeloid leukemias with 3,500 -5,500 new cases diagnosed annually (1, 2). The vast majority of APL patients harbor the chromosomal translocation t(15,17)(q22;q21) involving the retinoic acid receptor ␣ (RAR␣) gene on chromosome 15 and the promyelocytic leukemia (PML) gene on chromosome 17, generally giving rise to two fusion genes, PML-RAR␣ and RAR␣-PML (1, 3). Studies using transgenic mice have demonstrated that the protein product of the PML-RAR␣ fusion gene is primarily responsible for the leukemogenic property of this characteristic translocation (4, 5). All-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, can induce complete remission in most APL patients associated with an enhancement of differentiation pathways (6). Recent studies (7-9) have provided strong evidence that the induction of leukemia by the PML-RAR␣ protein relies on its ability to repress gene transcription by recruiting transcription repressor complexes. Pharmacological doses of ATRA stimulate the release of the transcription repressor complexes from PML-RAR␣, thereby activating the transcription of genes critical for normal granulocytic differentiation. However, ATRA is not curative, and resistance rapidly develops usually within 10 months of therapy (2, 6). Therefore, alternative therapies are necessary.Recently, As 2 O 3 was identified as a potent anti-leukemic agent for treating not only newly diagnosed but also relapsed APL patients (2, 10 -13), and it is remarkably effective in ATRA-refractory patients (2, 12). However, the mechanisms underlying its therapeutic effects are not well understood (2,...

Caspase-10 involvement in cytotoxic drug-induced apoptosis of tumor cells

“…Arsenic trioxide (As 2 O 3 ) upregulates casp-10 gene expression but the role of this event in As 2 O 3 -induced apoptosis remains unknown (Li et al, 2002). A caspase-10 requirement for chemotherapy-induced apoptosis has (b) HeLa, 293T and U937 cells were left untreated or treated with 4 mM As 2 O 3 for 48 h before immunoblot analysis of procaspase-9 (proC9) and -10 (proC10).…”

“…Chemotherapeutic agents such as etoposide and doxorubicin induce casp-10 gene transcription in a p53-dependent manner (Rikhof et al, 2003) and arsenic trioxide stimulates casp-10 gene transcription by promoting histone H3 phosphoacetylation in acute promyelocytic leukemia cells (Li et al, 2002). Recently, caspase-10 was shown to play a role in apoptosis induced by an anticancer drug, that is, paclitaxel, through a FADD-dependent mechanism (Park et al, 2004).…”

Retinoic acid and arsenic trioxide cooperate for apoptosis through phosphorylated RXR alpha

“…Although the mechanisms underlying most of the effects of As 2 O 3 are still not well understood, it is well established that As 2 O 3 is an oxidative stress agent (Kitchin and Ahmad, 2003), which, through the production of reactive oxygen species and the modification of thiol groups, induces protein and DNA damages (Meriin et al, 1999;Kapahi et al, 2000;Huang et al, 2004;Shi et al, 2004). These oxidative effects of As 2 O 3 result in the disruption of key signal transduction pathways, leading to the induction of apoptosis (Li et al, 2002). Indeed, As 2 O 3 activates the MAPK signaling pathways (Cavigelli et al, 1996;Meriin et al, 1999;Verma et al, 2002) and therefore induces the phosphorylation of a subset of transcription factors (AP-1, Elk, ATF2, CREB and others) (Bebien et al, 2003), PML (Hayakawa and Privalsky, 2004) and histones (Li et al, 2002(Li et al, , 2003aHe et al, 2003).…”

“…These oxidative effects of As 2 O 3 result in the disruption of key signal transduction pathways, leading to the induction of apoptosis (Li et al, 2002). Indeed, As 2 O 3 activates the MAPK signaling pathways (Cavigelli et al, 1996;Meriin et al, 1999;Verma et al, 2002) and therefore induces the phosphorylation of a subset of transcription factors (AP-1, Elk, ATF2, CREB and others) (Bebien et al, 2003), PML (Hayakawa and Privalsky, 2004) and histones (Li et al, 2002(Li et al, , 2003aHe et al, 2003). This leads to the increased transcription of critical apoptosisand proliferation-associated genes including among others, the proto-oncogenes c-fos, c-jun and Egr-1 (Lim et al, 1998;Bernstam and Nriagu, 2000;Liu et al, 2003) and caspases (Li et al, 2002).…”

Quantitative Mass Spectrometry Reveals Changes in Histone H2B Variants as Cells Undergo Inorganic Arsenic-Mediated Cellular Transformation

“…A number of studies have demonstrated that iAs exposure induces global and gene-specific post-translational histone modifications such as reduction of acetylation in histone H3 and H4: loss of H4Lys 16 10 and H2AX phosphorylation, and decreases in H2B ubiquitination (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”