NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

Deepanwita Sengupta; Liyong Zeng; Yumei Li; Simone Hausmann; Debopam Ghosh; Gang Yuan; Thuyen N Nguyen; Ruitu Lyu; Marcello Caporicci; Ana Morales Benitez; Garry L Coles; Vladlena Kharchenko; Iwona Czaban; Dulat Azhibek; Wolfgang Fischle; Mariusz Jaremko; Ignacio I Wistuba; Julien Sage; Lukasz Jaremko; Wei Li; Pawel K Mazur; Or Gozani

doi:10.1016/j.molcel.2021.08.034

NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

Deepanwita Sengupta, Liyong Zeng, Yumei Li, Simone Hausmann, Debopam Ghosh, Gang Yuan, Thuyen N Nguyen, Ruitu Lyu, Marcello Caporicci, Ana Morales Benitez, Garry L Coles, Vladlena Kharchenko, Iwona Czaban, Dulat Azhibek, Wolfgang Fischle, Mariusz Jaremko, Ignacio I Wistuba, Julien Sage, Lukasz Jaremko, Wei LiPawel K Mazur, Or Gozani

Research output: Contribution to journal › Article › peer-review

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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 NSD2$_{E1099K}$, 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.

Original language	English (US)
Journal	Molecular cell
DOIs	https://doi.org/10.1016/j.molcel.2021.08.034
State	Published - Sep 23 2021

Bibliographical note

KAUST Repository Item: Exported on 2021-09-27
Acknowledgements: 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.

ASJC Scopus subject areas

Cell Biology
Molecular Biology

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10.1016/j.molcel.2021.08.034

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Sengupta, D., Zeng, L., Li, Y., Hausmann, S., Ghosh, D., Yuan, G., Nguyen, T. N., Lyu, R., Caporicci, M., Morales Benitez, A., Coles, G. L., Kharchenko, V., Czaban, I., Azhibek, D., Fischle, W., Jaremko, M., Wistuba, I. I., Sage, J., Jaremko, L., ... Gozani, O. (2021). NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. Molecular cell. https://doi.org/10.1016/j.molcel.2021.08.034

@article{1dfb292b2410446696325a75ac9ff66d,

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 NSD2$_{E1099K}$, 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.",

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 Lukasz Jaremko and Wei Li and Mazur, {Pawel K} and Or Gozani",

note = "KAUST Repository Item: Exported on 2021-09-27 Acknowledgements: 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.",

year = "2021",

month = sep,

day = "23",

doi = "10.1016/j.molcel.2021.08.034",

language = "English (US)",

journal = "Molecular cell",

issn = "1097-2765",

publisher = "Elsevier",

}

Sengupta, D, Zeng, L, Li, Y, Hausmann, S, Ghosh, D, Yuan, G, Nguyen, TN, Lyu, R, Caporicci, M, Morales Benitez, A, Coles, GL, Kharchenko, V, Czaban, I, Azhibek, D, Fischle, W , Jaremko, M, Wistuba, II, Sage, J, Jaremko, L, Li, W, Mazur, PK & Gozani, O 2021, 'NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.', Molecular cell. https://doi.org/10.1016/j.molcel.2021.08.034

TY - JOUR

T1 - NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

AU - Sengupta, Deepanwita

AU - Zeng, Liyong

AU - Li, Yumei

AU - Hausmann, Simone

AU - Ghosh, Debopam

AU - Yuan, Gang

AU - Nguyen, Thuyen N

AU - Lyu, Ruitu

AU - Caporicci, Marcello

AU - Morales Benitez, Ana

AU - Coles, Garry L

AU - Kharchenko, Vladlena

AU - Czaban, Iwona

AU - Azhibek, Dulat

AU - Fischle, Wolfgang

AU - Jaremko, Mariusz

AU - Wistuba, Ignacio I

AU - Sage, Julien

AU - Jaremko, Lukasz

AU - Li, Wei

AU - Mazur, Pawel K

AU - Gozani, Or

N1 - KAUST Repository Item: Exported on 2021-09-27 Acknowledgements: 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.

PY - 2021/9/23

Y1 - 2021/9/23

N2 - 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 NSD2$_{E1099K}$, 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.

AB - 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 NSD2$_{E1099K}$, 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.

UR - http://hdl.handle.net/10754/671927

U2 - 10.1016/j.molcel.2021.08.034

DO - 10.1016/j.molcel.2021.08.034

M3 - Article

C2 - 34555356

SN - 1097-2765

JO - Molecular cell

JF - Molecular cell

ER -

NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

Abstract

Bibliographical note

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