Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions

Abstract

Background The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded. Methods In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes. Results In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction. Conclusions These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α over-activation.

Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation

“…Chromatin Immunoprecipitation (ChIP) assays were performed essentially as described before ( Coarfa et al, 2020 ; Maity et al, 2020 ; Wang J.N. et al, 2020 ; Wang S. et al, 2020 ; Marti et al, 2021 ). In brief, chromatin in control and treated cells were cross-linked with 1% formaldehyde.…”

A KDM4-DBC1-SIRT1 Axis Contributes to TGF-b Induced Mesenchymal Transition of Intestinal Epithelial Cells

“…Chromatin Immunoprecipitation (ChIP) assays were performed essentially as described before ( Coarfa et al, 2020 ; Hu et al, 2020 ; Jehanno et al, 2020 ; Maity et al, 2020 ; Mallik et al, 2020 ; Moon et al, 2020 ; Shen et al, 2020 ; Wang J. N. et al, 2020 ; Wang S. et al, 2020 ; Zhang et al, 2020 ; Zhao et al, 2020 ; Marti et al, 2021 ; Peng et al, 2021 ; Rashid et al, 2021 ). In brief, chromatin in control and treated cells were cross-linked with 1% formaldehyde.…”

The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions

“…PARP-1 also contributes to HIF-1α accumulation in response to hypoxia, and this response is mediated by nitric oxide [ 21 , 22 ]. PARP1 physically interacts with HIF-1α, PARylates the transcription factor, and functions as a stability regulator and transcriptional coactivator in HIF-1α-dependent gene expression [ 23 , 24 , 25 ] ( Figure 1 ). Accordingly, the expression of key HIF-1 target genes and the transcriptional activity of HIF-1 are compromised by PARP inhibition or in PARP-1 −/− cells [ 26 ].…”