Department of Oncology, Institute of Medical Sciences, National Clinical Research Center for Geriatric Disorders, Institue of Medical Sciences, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
Adv Sci (Weinh). 2024 Oct;11(38):e2400381. doi: 10.1002/advs.202400381. Epub 2024 Aug 9.
Histones methyltransferase NSD3 targeting H3K36 is frequently disordered and mutant in various cancers, while the function of NSD3 during cancer initiation and progression remains unclear. In this study, it is proved that downregulated level of NSD3 is linked to clinical features and poor survival in lung adenocarcinoma. In vivo, NSD3 inhibited the proliferation, immigration, and invasion ability of lung adenocarcinoma. Meanwhile, NSD3 suppressed glycolysis by inhibiting HK2 translation, transcription, glucose uptake, and lactate production in lung adenocarcinoma. Mechanistically, as an intermediary, NSD3 binds to PPP1CB and p-STAT3 in protein levels, thus forming a trimer to dephosphorylate the level of p-STAT3 by PPP1CB, leading to the suppression of HK2 transcription. Interestingly, the phosphorylation function of PPP1CB is related to the concentration of carbon dioxide and pH value in the culture environment. Together, this study revealed the critical non-epigenetic role of NSD3 in the regulation of STAT3-dependent glycolysis, providing a piece of compelling evidence for targeting the NSD3/PPP1CB/p-STAT3 in lung adenocarcinoma.
组蛋白甲基转移酶 NSD3 靶向 H3K36 在各种癌症中经常发生紊乱和突变，而 NSD3 在癌症发生和进展过程中的功能仍不清楚。在这项研究中，证明 NSD3 的下调水平与肺腺癌的临床特征和不良预后相关。在体内，NSD3 抑制肺腺癌的增殖、迁移和侵袭能力。同时，NSD3 通过抑制 HK2 的翻译、转录、葡萄糖摄取和乳酸生成来抑制肺腺癌细胞的糖酵解。在机制上，作为一种中介，NSD3 在蛋白质水平上与 PPP1CB 和 p-STAT3 结合，从而形成三聚体通过 PPP1CB 去磷酸化 p-STAT3 的水平，从而抑制 HK2 的转录。有趣的是，PPP1CB 的磷酸化功能与培养环境中的二氧化碳浓度和 pH 值有关。总之，这项研究揭示了 NSD3 在调节 STAT3 依赖性糖酵解中的关键非表观遗传作用，为靶向 NSD3/PPP1CB/p-STAT3 治疗肺腺癌提供了有力证据。
