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It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC<jats:sub>50<\/jats:sub> values of 10.8, 7.9 and 7.0\u2009n<jats:sc>m<\/jats:sc> in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase\/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase\/AKT\/mammalian target of rapamycin (PI3K\/AKT\/mTOR) and \u03b2-catenin pro-survival pathways were inhibited. The decreased level of \u03b2-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies.<\/jats:p>","DOI":"10.1038\/bcj.2015.83","type":"journal-article","created":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T13:22:20Z","timestamp":1445001740000},"page":"e357-e357","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Romidepsin targets multiple survival signaling pathways in malignant T cells"],"prefix":"10.1038","volume":"5","author":[{"given":"B C","family":"Valdez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J E","family":"Brammer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Murray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Hosing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Nieto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R E","family":"Champlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B S","family":"Andersson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,16]]},"reference":[{"key":"BFbcj201583_CR1","doi-asserted-by":"publisher","first-page":"301","DOI":"10.7164\/antibiotics.47.301","volume":"47","author":"H Ueda","year":"1994","unstructured":"Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T et al. 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