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.
[Display omitted]
•High NSD2 and H3K36me2 levels common to lung cancer and correlate with poor prognosis•NSD2-selective H3K36me2 catalysis promotes rapid malignant tumor progression in vivo•A versatile CRISPRi-based in vivo system developed to test gene function in LUAD•NSD2 knockdown combined with MEK1/2 inhibitor results in sustained tumor regression
NSD2 is a key epigenetic enzyme that generates the canonical histone modification H3K36me2. Sengupta et al. show that NSD2 hyperactivity promotes aggressive malignant lung tumor pathogenesis in vivo and uncover a mechanism by which lung cancers become dependent on an NSD2-H3K36me2 axis to sustain transcriptional programs driving tumorigenesis.