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 journalArticlepeer-review

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 languageEnglish (US)
JournalMolecular cell
DOIs
StatePublished - Sep 23 2021

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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