Researchers identified a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the Hedgehog/GLI (HH/GLI) pathway, providing a novel mechanism of non-canonical Smoothened-independent activation of HH/GLI signaling in melanoma.
[Oncogene]
7753456
{7753456:EWJW64V7}
apa
50
1
162043
https://www.stemcellsciencenews.com/wp-content/plugins/zotpress/
%7B%22status%22%3A%22success%22%2C%22updateneeded%22%3Afalse%2C%22instance%22%3A%22zotpress-ad0ababfefddee104b9c6279c245784c%22%2C%22meta%22%3A%7B%22request_last%22%3A0%2C%22request_next%22%3A0%2C%22used_cache%22%3Atrue%7D%2C%22data%22%3A%5B%7B%22key%22%3A%22EWJW64V7%22%2C%22library%22%3A%7B%22id%22%3A7753456%7D%2C%22meta%22%3A%7B%22creatorSummary%22%3A%22Pietrobono%20et%20al.%22%2C%22parsedDate%22%3A%222021-05-06%22%2C%22numChildren%22%3A0%7D%2C%22bib%22%3A%22%3Cdiv%20class%3D%5C%22csl-bib-body%5C%22%20style%3D%5C%22line-height%3A%202%3B%20padding-left%3A%201em%3B%20text-indent%3A-1em%3B%5C%22%3E%5Cn%20%20%3Cdiv%20class%3D%5C%22csl-entry%5C%22%3EPietrobono%2C%20S.%2C%20Gaudio%2C%20E.%2C%20Gagliardi%2C%20S.%2C%20Zitani%2C%20M.%2C%20Carrassa%2C%20L.%2C%20Migliorini%2C%20F.%2C%20Petricci%2C%20E.%2C%20Manetti%2C%20F.%2C%20Makukhin%2C%20N.%2C%20Bond%2C%20A.%20G.%2C%20Paradise%2C%20B.%20D.%2C%20Ciulli%2C%20A.%2C%20Fernandez-Zapico%2C%20M.%20E.%2C%20Bertoni%2C%20F.%2C%20%26amp%3B%20Stecca%2C%20B.%20%282021%29.%20Targeting%20non-canonical%20activation%20of%20GLI1%20by%20the%20SOX2-BRD4%20transcriptional%20complex%20improves%20the%20efficacy%20of%20HEDGEHOG%20pathway%20inhibition%20in%20melanoma.%20%3Ci%3EOncogene%3C%5C%2Fi%3E%2C%201%26%23x2013%3B16.%20%3Ca%20href%3D%27https%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41388-021-01783-9%27%3Ehttps%3A%5C%2F%5C%2Fdoi.org%5C%2F10.1038%5C%2Fs41388-021-01783-9%3C%5C%2Fa%3E%20%3Ca%20title%3D%27Cite%20in%20RIS%20Format%27%20class%3D%27zp-CiteRIS%27%20href%3D%27https%3A%5C%2F%5C%2Fwww.stemcellsciencenews.com%5C%2Fwp-content%5C%2Fplugins%5C%2Fzotpress%5C%2Flib%5C%2Frequest%5C%2Frequest.cite.php%3Fapi_user_id%3D7753456%26amp%3Bitem_key%3DEWJW64V7%27%3ECite%3C%5C%2Fa%3E%20%3C%5C%2Fdiv%3E%5Cn%3C%5C%2Fdiv%3E%22%2C%22data%22%3A%7B%22itemType%22%3A%22journalArticle%22%2C%22title%22%3A%22Targeting%20non-canonical%20activation%20of%20GLI1%20by%20the%20SOX2-BRD4%20transcriptional%20complex%20improves%20the%20efficacy%20of%20HEDGEHOG%20pathway%20inhibition%20in%20melanoma%22%2C%22creators%22%3A%5B%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Silvia%22%2C%22lastName%22%3A%22Pietrobono%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Eugenio%22%2C%22lastName%22%3A%22Gaudio%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Sinforosa%22%2C%22lastName%22%3A%22Gagliardi%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Mariapaola%22%2C%22lastName%22%3A%22Zitani%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Laura%22%2C%22lastName%22%3A%22Carrassa%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Francesca%22%2C%22lastName%22%3A%22Migliorini%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Elena%22%2C%22lastName%22%3A%22Petricci%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Fabrizio%22%2C%22lastName%22%3A%22Manetti%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Nikolai%22%2C%22lastName%22%3A%22Makukhin%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Adam%20G.%22%2C%22lastName%22%3A%22Bond%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Brooke%20D.%22%2C%22lastName%22%3A%22Paradise%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Alessio%22%2C%22lastName%22%3A%22Ciulli%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Martin%20E.%22%2C%22lastName%22%3A%22Fernandez-Zapico%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Francesco%22%2C%22lastName%22%3A%22Bertoni%22%7D%2C%7B%22creatorType%22%3A%22author%22%2C%22firstName%22%3A%22Barbara%22%2C%22lastName%22%3A%22Stecca%22%7D%5D%2C%22abstractNote%22%3A%22Despite%20the%20development%20of%20new%20targeted%20and%20immune%20therapies%2C%20the%20prognosis%20of%20metastatic%20melanoma%20remains%20bleak.%20Therefore%2C%20it%20is%20critical%20to%20better%20understand%20the%20mechanisms%20controlling%20advanced%20melanoma%20to%20develop%20more%20effective%20treatment%20regimens.%20Hedgehog%5C%2FGLI%20%28HH%5C%2FGLI%29%20signaling%20inhibitors%20targeting%20the%20central%20pathway%20transducer%20Smoothened%20%28SMO%29%20have%20shown%20to%20be%20clinical%20efficacious%20in%20skin%20cancer%3B%20however%2C%20several%20mechanisms%20of%20non-canonical%20HH%5C%2FGLI%20pathway%20activation%20limit%20their%20efficacy.%20Here%2C%20we%20identify%20a%20novel%20SOX2-BRD4%20transcriptional%20complex%20driving%20the%20expression%20of%20GLI1%2C%20the%20final%20effector%20of%20the%20HH%5C%2FGLI%20pathway%2C%20providing%20a%20novel%20mechanism%20of%20non-canonical%20SMO-independent%20activation%20of%20HH%5C%2FGLI%20signaling%20in%20melanoma.%20Consistently%2C%20we%20find%20a%20positive%20correlation%20between%20the%20expression%20of%20GLI1%20and%20SOX2%20in%20human%20melanoma%20samples%20and%20cell%20lines.%20Further%2C%20we%20show%20that%20combined%20targeting%20of%20canonical%20HH%5C%2FGLI%20pathway%20with%20the%20SMO%20inhibitor%20MRT-92%20and%20of%20the%20SOX2-BRD4%20complex%20using%20a%20potent%20Proteolysis%20Targeted%20Chimeras%20%28PROTACs%29-derived%20BRD4%20degrader%20%28MZ1%29%2C%20yields%20a%20synergistic%20anti-proliferative%20effect%20in%20melanoma%20cells%20independently%20of%20their%20BRAF%2C%20NRAS%2C%20and%20NF1%20mutational%20status%2C%20with%20complete%20abrogation%20of%20GLI1%20expression.%20Combination%20of%20MRT-92%20and%20MZ1%20strongly%20potentiates%20the%20antitumor%20effect%20of%20either%20drug%20as%20single%20agents%20in%20an%20orthotopic%20melanoma%20model.%20Together%2C%20our%20data%20provide%20evidence%20of%20a%20novel%20mechanism%20of%20non-canonical%20activation%20of%20GLI1%20by%20the%20SOX2-BRD4%20transcriptional%20complex%2C%20and%20describe%20the%20efficacy%20of%20a%20new%20combinatorial%20treatment%20for%20a%20subset%20of%20melanomas%20with%20an%20active%20SOX2-BRD4-GLI1%20axis.%22%2C%22date%22%3A%222021-05-06%22%2C%22language%22%3A%22en%22%2C%22DOI%22%3A%2210.1038%5C%2Fs41388-021-01783-9%22%2C%22ISSN%22%3A%221476-5594%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fwww.nature.com%5C%2Farticles%5C%2Fs41388-021-01783-9%22%2C%22deleted%22%3A1%2C%22collections%22%3A%5B%22DUPVZUHA%22%5D%2C%22dateModified%22%3A%222021-05-06T17%3A19%3A44Z%22%7D%7D%5D%7D
Pietrobono, S., Gaudio, E., Gagliardi, S., Zitani, M., Carrassa, L., Migliorini, F., Petricci, E., Manetti, F., Makukhin, N., Bond, A. G., Paradise, B. D., Ciulli, A., Fernandez-Zapico, M. E., Bertoni, F., & Stecca, B. (2021). Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma. Oncogene, 1–16. https://doi.org/10.1038/s41388-021-01783-9 Cite
