GSE210455
Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes [ChIP-seq]
The involvement of G-Protein-Coupled Receptors' (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its PM counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than PM localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for flag tag targeting the C or N terminal region of Hcar1 in HeLa cells with lactate or PBS. Both C- and N-terminus flag tagged cells were used for ChIP-seq studies. Two samples from each terminus tagged cells were used for either lactate or vehicle (PBS); in total 4 samples per treatment group (C and N terminal flag ChIP seq duplicates were grouped and compared to input), and only shared peaks between C and N were used for further bioinformatic analysis.