Complex context relationships between DNA methylation and accessibility, histone marks, and hTERT gene expression in acute promyelocytic leukemia cells: perspectives for all-trans retinoic acid in cancer therapy.

Telomerase (hTERT) reactivation and sustained expression is a key event in the process of cellular transformation. Therefore, the identification of the mechanisms regulating hTERT expression is of great interest for the development of new anticancer therapies. Although the epigenetic state of hTERT gene promoter is important, we still lack a clear understanding of the mechanisms by which epigenetic changes affect hTERT expression. Retinoids are well-known inducers of granulocytic maturation in acute promyelocytic leukemia (APL). We have previously shown that retinoids repressed hTERT expression in the absence of maturation leading to growth arrest and cell death. Exploring the mechanisms of this repression, we showed that transcription factor binding was dependent on the epigenetic status of hTERT promoter. In the present study, we used APL cells lines and publicly available datasets from APL patients to further investigate the integrated epigenetic events that promote hTERT promoter transition from its silent to its active state, and inversely. We showed, in APL patients, that the methylation of the distal domain of hTERT core promoter was altered and correlated with the outcome of the disease. Further studies combining complementary approaches carried out on APL cell lines highlighted the significance of a domain outside the minimal promoter, localized around 5 kb upstream from the transcription start site, in activating hTERT. This domain is characterized by DNA hypomethylation and H3K4Me3 deposition. Our findings suggest a cooperative interplay between hTERT promoter methylation, chromatin accessibility, and histone modifications that force the revisiting of previously proposed concepts regarding hTERT epigenetic regulation. They represent, therefore, a major advance in predicting sensitivity to retinoid-induced hTERT repression and, more generally, in the potential development of therapies targeting hTERT expression in cancers.

Neurotensin regulation induces overexpression and activation of EGFR in HCC and restores response to erlotinib and sorafenib.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer due to the combination of late diagnosis and a lack of curative treatments. The identification of factors which promote tumor aggressiveness, and those that predict treatment responses, are a means to optimize the management of HCC patients. The complex of Neurotensin (NTS) and its high affinity receptor (NTSR1) has been shown to induce tumor growth and metastasis process in various cancers. In this paper, we propose that NTS and NTSR1 can assist in the management of HCC. Concomitant expression of NTS/NTSR1 was correlated with poor prognosis and found in 50% of HCC patients. We show that NTSR1 expression was positively correlated with the alteration of the Wnt/ß-catenin pathway. Its activation creates EGFR driver activation which consequently enhances tumor progression, and sensitizes HCC tumor cells to TKI, such as sorafenib. The NTS/NTSR1 complex is a potential drug target for HCC, because it is an upstream regulator in the chain of cellular events involved in HCC progression. It could also be used as a theranostic biomarker for sorafenib to improve the HCC patient management.