A metabolic prosurvival role for PML in breast cancer
A metabolic prosurvival role for PML in breast cancer
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DOI：
10.1172/jci62129
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Pandolfi, Pier P.
中科院分区：
文献类型：
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作者：
Carracedo, Arkaitz;Weiss, Dror;Pandolfi, Pier P.
癌细胞表现出异常代谢，其促进生物质的更有效产生，从而促进肿瘤生长和进展。然而，调节这种代谢开关的遗传线索在很大程度上仍然不确定。我们确定了早幼粒细胞白血病（PML）基因的代谢功能，揭示了这种真正的肿瘤抑制因子在乳腺癌细胞存活中的意想不到的作用。我们发现PML采取了行动。作为PPAR γ共激活因子1A（PGC1A）乙酰化的负调节剂和PPAR信号传导和脂肪酸氧化的有效激活剂。我们进一步表明PML促进ATP产生并抑制失巢凋亡。重要的是，PML表达允许3D基底膜乳腺培养模型中的管腔填充，这一效应通过脂肪酸氧化的药理学抑制而逆转。此外，乳腺癌活检组织的免疫组化分析显示，PML在乳腺癌的一个子集中过表达，并在三阴性病例中富集。事实上，乳腺癌中的PML表达与复发时间的缩短、预后不良的基因特征和激活的PPAR信号传导显着相关。这些发现具有重要的治疗意义，因为PML及其在脂肪酸氧化代谢中的关键作用可通过药理学抑制来实现，这是一种潜在的未来癌症预防和治疗模式。
Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted. as both a negative regulator of PPAR gamma coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.