Lactylation of LSD1 is an acquired epigenetic vulnerability of BRAFi/MEKi-resistant melanoma [RNA-seq]

BRAFV600E mutant melanomas treated with BRAF inhibitor (Dabrafenib) and MEK inhibitor (Trametinib) almost invariably develop drug resistance (DTR). Restored glycolysis, frequently found in clinical targeted therapy-resistant melanoma biopsies, has been shown to elicit drug resistance. How resumed glycolysis controls the emergence of acquired resistance, especially via intrinsic mechanisms that circumvent the BRAF/MEK module, remains unknown. Here, we identify lactylation of LSD1, induced by re-accumulated lactate in DTR melanoma cells, selectively drives survival via epigenetic reprogramming. Mechanistically, lactylation of LSD1 promotes its interaction with FosL1, thereby preventing its ubiquitination and degradation by E3 ligase tripartite-motif-containing protein 21 (TRIM21). In DTR melanoma cells, chromatin binding capacity of FosL1 was significantly strengthened due to reduced acetylation, which in turn increases selective chromatin enrichment of LSD1. We further demonstrate that lactylated LSD1 co-orchestrates gene transcription with FosL1 to repress ferroptosis in DTR cells via interfering with transferrin receptor protein 1 (TFRC)-mediated iron uptake. LSD1 inhibitor (LSD1i) activates ferroptosis, resulting in drastic DTR melanoma regression in mice. Importantly, LSD1i-induced immunogenic ferroptosis synergizes with immune checkpoint blockade (ICB) in vivo. Together, our results highlight a crucial role of metabolic rewiring-induced epigenetic reprogramming as a bypass resistance mechanism in DTR melanoma, which provides a therapeutically actionable strategy to overcome acquired resistance to targeted therapy. Overall design: RNA-seq was perform to obtain LSD1-/FosL1-dependent transcriptomic signatures

BRAFV600E突变型黑色素瘤经BRAF抑制剂（达拉非尼，Dabrafenib）与MEK抑制剂（曲美替尼，Trametinib）治疗后，几乎均会产生药物耐药性（drug resistance，以下简称DTR）。
临床靶向治疗耐药黑色素瘤活检样本中常见的恢复型糖酵解，已被证实可诱发药物耐药性。
然而，恢复的糖酵解如何调控获得性耐药的产生，尤其是通过规避BRAF/MEK信号模块的内在机制实现这一过程，目前仍不明确。
本研究证实，DTR黑色素瘤细胞中由乳酸再蓄积诱导的赖氨酸特异性去甲基化酶1（LSD1）乳酸化修饰，可通过表观遗传重编程选择性促进细胞存活。
机制层面，LSD1的乳酸化修饰可增强其与FosL1的相互作用，从而阻止其被E3泛素连接酶三联基序蛋白21（TRIM21）泛素化并降解。
在DTR黑色素瘤细胞中，FosL1的染色质结合能力因乙酰化水平降低而显著增强，进而提升了LSD1的选择性染色质富集能力。
本研究进一步发现，乳酸化修饰的LSD1可与FosL1协同调控基因转录，通过干扰转铁蛋白受体蛋白1（TFRC）介导的铁摄取过程，抑制DTR细胞的铁死亡。
LSD1抑制剂（LSD1i）可激活铁死亡，使小鼠体内的DTR黑色素瘤出现显著消退。
重要的是，LSD1i诱导的免疫原性铁死亡在体内可与免疫检查点阻断（ICB）产生协同效应。
综上，本研究结果表明，代谢重编程诱导的表观遗传重编程作为DTR黑色素瘤的旁路耐药机制发挥关键作用，为克服靶向治疗获得性耐药提供了可转化的治疗策略。
实验整体设计：通过RNA测序（RNA-seq）获取依赖于LSD1和FosL1的转录组特征谱。