@article{da594ad638e442799fca8950c66dd241,
title = "NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis",
abstract = "The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.",
keywords = "CRISPR interference mouse model, H3K36, KRAS, MEK inhibition, NSD2, chromatin, epigenetics, histone methylation, lung adenocarcinoma, lung cancer",
author = "Deepanwita Sengupta and Liyong Zeng and Yumei Li and Simone Hausmann and Debopam Ghosh and Gang Yuan and Nguyen, {Thuyen N.} and Ruitu Lyu and Marcello Caporicci and {Morales Benitez}, Ana and Coles, {Garry L.} and Vladlena Kharchenko and Iwona Czaban and Dulat Azhibek and Wolfgang Fischle and Mariusz Jaremko and Wistuba, {Ignacio I.} and Julien Sage and {\L}ukasz Jaremko and Wei Li and Mazur, {Pawel K.} and Or Gozani",
note = "Funding Information: We thank members of the Gozani and Mazur labs for critical reading of the manuscript. This work was supported in part by grants from the NIH ( R35 GM139569 to O.G., R01 CA236118 to O.G. and P.K.M., K99 CA255936 to S.M., and R01HG007538 , R01CA193466 , and R01CA228140 to W.L.); intramural funds from KAUST (to W.F., L.J., and M.J.); and AACR , NETRF , a DOD PRCRP career development award ( CA181486 ), a career enhancement grant from The University of Texas NIH SPORE in Lung Cancer ( P50CA070907 ), and the Andrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer Research ( RR160078 ) (to P.K.M.). D.S. was supported by a grant from the Stanford Maternal and Child Health Research Institute . This work was also supported in part by the Stanford Cancer Institute , a NCI-designated Comprehensive Cancer Center. Funding Information: We thank members of the Gozani and Mazur labs for critical reading of the manuscript. This work was supported in part by grants from the NIH (R35 GM139569 to O.G. R01 CA236118 to O.G. and P.K.M. K99 CA255936 to S.M. and R01HG007538, R01CA193466, and R01CA228140 to W.L.); intramural funds from KAUST (to W.F. L.J. and M.J.); and AACR, NETRF, a DOD PRCRP career development award (CA181486), a career enhancement grant from The University of Texas NIH SPORE in Lung Cancer (P50CA070907), and the Andrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer Research (RR160078) (to P.K.M.). D.S. was supported by a grant from the Stanford Maternal and Child Health Research Institute. This work was also supported in part by the Stanford Cancer Institute, a NCI-designated Comprehensive Cancer Center. D.S. L.Z. and Y.L. were responsible for experimental design, execution, data analysis, and manuscript preparation. D.S. performed CUT&RUN and RNA-seq experiments, and Y.L analyzed RNA-seq and CUT&RUN data under the supervision of W.L. and in coordination with D.S. R.L. analyzed lung RNA-seq data. S.H. performed PDX and IHC analyses. M.C. and A.M.B. assisted L.Z. with CRISPRi transgenic experiments and tissue analyses. D.G. T.N.N. and G.L.C. helped D.S. with NSD2 transgenic experiments with supervision from J.S. G.Y. performed full-length NSD2 methylation assays. V.K. I.C. D.A. W.F. M.J. and L.J. performed nucleosome and SAM binding affinity experiments. I.I.W. evaluated histopathology. J.S. helped with manuscript preparation. O.G. P.K.M. and W.L. were equally responsible for supervision of the research, data interpretation, and manuscript preparation. O.G. is a co-scientific founder, consultant, and stockholder of EpiCypher, Inc. and K36 Therapeutics, Inc. P.K.M. is a scientific co-founder, consultant, and stockholder of Amplified Medicines, Inc. and Ikena Oncology, Inc. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = nov,
day = "4",
doi = "10.1016/j.molcel.2021.08.034",
language = "English (US)",
volume = "81",
pages = "4481--4492.e9",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "21",
}