Project description:HSF1 orchestrates the heat shock response pathway. This pathway is co-opted in cancer and provides critical stress relief from oncogenic stress. HSF1 has a diverse occupancy signature depending on the cell type. In this study, we performed HSF1 ChIP-seq analysis using the human T-ALL cell line CUTLL1 and P12. These results revealed the HSF1 chromatin binding signature in CUTLL1 and P12 cells. MYC is a driving oncogene in T-ALL. The non-oncogene addiction pathways that act downstream of this transcription factor to support anabolic pathways are not well-understood. For this reason, we performed MYC ChIP-seq analysis using the human T-ALL cell line CUTLL1. These results revealed that HSF1 and HSF1 targets are included in the MYC binding signature.
Project description:Our data demonstrate binding of NOTCH1 on the promoters of HSF1 and HSF1 targets. We performed RNA-seq upon control conditions, inhibition of the NOTCH1 pathway by gSI, HSF1 knockdown and combination of HSF1 knockdown and gSI treatment. Our results show that NOTCH1 regulates the expression of heat shock response genes. Moreover, combination of HSF1 downregulation and gSI treatment further decreased the expression of heat shock response genes compared to single treatments.
Project description:Cellular transformation is accompanied by extensive rewiring of many biological processes leading to augmented levels of distinct types of cellular stress, including proteotoxic stress. Cancer cells critically depend on stress-relief pathways for their survival. However, the mechanisms underlying the transcriptional initiation and maintenance of the oncogenic stress response remain elusive. Here, we show that the expression of heat shock transcription factor 1 (HSF1) and the downstream mediators of the heat shock response is transcriptionally upregulated in T cell acute lymphoblastic leukemia (T-ALL). Hsf1 ablation suppresses the growth of human T-ALL and eradicates leukemia in mouse models of T-ALL, while sparing normal hematopoiesis. HSF1 drives a compact transcriptional program and among the direct HSF1 targets, specific chaperones and co-chaperones mediate its critical role in T-ALL. Notably, we demonstrate that the central T-ALL oncogene NOTCH1 hijacks the cellular stress response machinery by inducing the expression of HSF1 and its downstream effectors. The NOTCH1 signaling status controls the levels of chaperone/co-chaperone complexes and predicts the response of T-ALL patient samples to HSP90 inhibition. Our data demonstrate an integral crosstalk between mediators of oncogene and non-oncogene addiction and reveal critical nodes of the heat shock response pathway that can be targeted therapeutically.
Project description:Oncogenes NOTCH1 and MYC directly regulate HSF1 and other critical proteins of the stress-response pathway in T-ALL. This GRO-Seq experiment demonstrates that release from NOTCH1 inhibition results in upregulation of HSF1 and other key HSPs.
