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NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis
Deepanwita Sengupta1, Liyong Zeng2, Yumei Li3
1Department of Biology, Stanford University, Stanford, CA 94305, USA.
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.
Insights
NSD2
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- The role of NSD2 in solid tumors, particularly lung adenocarcinoma (LUAD), is not fully understood.
- Oncogenic KRAS signaling is a key driver in LUAD pathogenesis.
Purpose of the Study:
- To investigate the etiological role of NSD2 enzymatic activity in LUAD.
- To explore the interplay between NSD2 and KRAS signaling in LUAD development.
- To identify NSD2 as a potential therapeutic target for LUAD.
Main Methods:
- Utilized in vivo CRISPRi-based system for gene function testing in LUAD mouse models.
- Assessed the impact of NSD2 expression and knockdown on tumor progression and survival.
- Investigated the epigenetic modifications (H3K36me2) mediated by NSD2.
- Evaluated therapeutic strategies combining NSD2 depletion with MEK1/2 inhibition.
Main Results:
- NSD2 enzymatic activity, specifically H3K36me2 catalysis, cooperates with KRAS signaling to drive LUAD.
- A hyperactive NSD2 variant accelerates tumor progression and reduces survival in KRAS-driven LUAD models.
- NSD2 amplifies KRAS and other oncogenic gene expression programs.
- NSD2 loss or knockdown significantly attenuates LUAD tumor progression and neoplastic growth in patient-derived xenografts (PDXs).
- Combined NSD2 depletion and MEK1/2 inhibition led to near-complete LUAD tumor regression.
Conclusions:
- NSD2 is a crucial epigenetic regulator in LUAD pathogenesis, sustaining oncogenic signaling.
- The NSD2-H3K36me2 axis is a pivotal player in KRAS-driven LUAD.
- NSD2 represents a promising therapeutic target for LUAD treatment.
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