Abstract
Tumor hypoxia contributes to a biologically aggressive phenotype and therapeutic resistance. Recent studies have revealed that hypoxia reduces expression of several DNA damage recognition and repair (DRR) genes via both hypoxia-inducible factor (HIF)-independent and -dependent pathways, and this induced genomic instability in cancer cells. We show here that one of the HIF-target genes—differentiated embryo chondrocyte (DEC)—plays a role in DNA damage response via transcriptional repression. Comprehensive gene expression and database analyses have revealed systemic repression of DNA-DRR genes in cancer and non-cancer cells under hypoxic conditions. Hypoxic repression in typical cases was confirmed by quantitative RT-PCR and promoter reporter experiments, and knockdown experiments indicated the critical role of DEC2 in such repression. Assessment of histone H2AX phosphorylation revealed that recognition and repair of DNA double-strand breaks (DSBs) induced by bleomycin or γ-ray irradiation were attenuated; moreover, Cleaved Caspase-3 levels were decreased with pre-conditioning under hypoxia: opposing phenomena were ascertained by knockdown of DEC2. Finally, pre-conditioning under hypoxia decreased the sensitivity of cancer cells to DSBs, and knockdown of DEC2 increased γ-ray sensitivity. These data imply that a critical reduction of DNA-DRR occurs via DEC-dependent transcriptional repression and suggest that DEC is a potential molecular target for anti-cancer strategies.
Highlights
Hypoxia is one of the hallmarks of growing solid tumors
We and others reported that the hypoxia-inducible factor (HIF)-differentiated embryo chondrocyte (DEC) signaling pathway -whereby HIF-1 induces DEC1 and DEC2- plays an important role in transcriptional repression of the mismatch repair gene MLH1 under hypoxic conditions [15, 16]
We demonstrate for the first time that DEC1 and DEC2 are involved in the transcriptional repression of many DNA-damage recognition and repair (DRR) genes under hypoxic conditions
Summary
Hypoxia is one of the hallmarks of growing solid tumors. The tumor microenvironment is known to play a critical role in the development of biologically aggressive tumor phenotypes, and their resistance to chemo- and radio-therapy, through altered expression of various genes [1,2,3,4]. We and others reported that the HIF-DEC signaling pathway -whereby HIF-1 induces DEC1 ( called BHLHE40, STRA13, or SHARP2) and DEC2 ( called BHLHE41 or SHARP1)- plays an important role in transcriptional repression of the mismatch repair gene MLH1 under hypoxic conditions [15, 16]. Recent publications have shown that expression of several DNA damage recognition and repair (DRR) genes -MLH1, RAD51, BRCA1, MSH2 and NBS1-decreases under hypoxic conditions via HIF-1-dependent and -independent mechanisms, and that this repression of DNA-DRR leads to genomic instability, carcinogenesis, tumor progression, and treatment failure [21,22,23,24,25,26,27]. The precise functional role of the HIF-DEC signaling pathway, especially in hypoxic repression of DNA-DRR gene expression, is not yet fully understood
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