ETS family transcriptional regulators drive chromatin dynamics and malignancy in squamous cell carcinomas

Abstract

Tumor-initiating stem cells (SCs) exhibit distinct patterns of transcription factors and gene expression compared to healthy counterparts. Here, we show that dramatic shifts in large open-chromatin domain (super-enhancer) landscapes underlie these differences and reflect tumor microenvironment. By in vivo super-enhancer and transcriptional profiling, we uncover a dynamic cancer-specific epigenetic network selectively enriched for binding motifs of a transcription factor cohort expressed in squamous cell carcinoma SCs (SCC-SCs). Many of their genes, including Ets2 and Elk3, are themselves regulated by SCC-SC super-enhancers suggesting a cooperative feed-forward loop. Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs. ETS2-deficiency disrupts the SCC-SC super-enhancer landscape and downstream cancer genes while ETS2-overactivation in epidermal-SCs induces hyperproliferation and SCC super-enhancer-associated genes Fos, Junb and Klf5. Together, our findings unearth an essential regulatory network required for the SCC-SC chromatin landscape and unveil its importance in malignant progression.DOI: http://dx.doi.org/10.7554/eLife.10870.001

Translation from unconventional 5′ start sites drives tumour initiation

“…If this hypothesis is correct, then we should see differential uORF usage in established cancers. We therefore examined uORF usage in a tumour allograft model, in which oncogenic HRAS G12V in combination with loss of TGFβ receptor II rapidly progresses in a SOX2-dependent manner into SCCs 25 (Extended Data Fig. 6d).…”

“…To test whether eIF2A is required for translation in SCCs, we used CRISPR/Cas9 to establish three independent Eif2a- null clones of Hras G12V ;Tgfbr2- null SCCs 25 (Fig. 5a, Extended Data Fig.…”

TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma

“…Indeed, Nrf2 signaling can be induced by many mechanisms (Ma, 2013), including activating Nrf2 and inactivating Keap1 mutations (Cancer Genome Atlas Network, 2015), oncogenic Ras (DeNicola et al, 2011), and ectopically expressed Sox2 in normal keratinocytes (Sendoel et al, 2017). Furthermore, identification of a SCC specific super enhancer driving Nrf2 transcription in Hras G12V initiated, Tgfbr2 -deficient SCCs suggest TGFβ independent mechanisms (Yang et al, 2015). These data call into question whether the heterogeneous response to chemotherapy and progression after treatment can solely be explained by Nrf2/Glutathione expression, or whether these metabolic features require additional, unknown mechanisms that would endow a smaller subset of TPCs with the ability to resist treatment and initiate recurrent SCC growths.…”

PI3K/Akt/mTOR activation by suppression of ELK3 mediates chemosensitivity of MDA-MB-231 cells to doxorubicin by inhibiting autophagy

“…ELK3 is highly expressed in the nuclei of well-differentiated primary tumor cells, but it is expressed in the cytoplasm of metastatic lymph node cells [6]. Recently, it was reported that ELK3 expression promotes malignant progression of squamous cell carcinoma and that suppression of ELK3 severely impairs tumor growth [7].…”