Homeobox基因家族与胚胎发育和器官形态发生有关。证据表明，这些Homeobox基因在突变或过度表达时也对促进肿瘤发生至关重要。其中之一，成对的同源结构域转录因子-2（PITX2），除了其不同的发育调节功能外，还参与了癌症的调控。PITX2早期显示能够通过激活不同的信号级联，诱导卵巢癌细胞增殖。增加癌细胞增殖需要不断提供三磷酸腺苷和生物量合成的营养物质，这由包括增强葡萄糖摄取和增加糖酵解速率在内的改变性癌细胞代谢来促进。本研究突出了PITX2在通过蛋白激酶B-磷酸化（磷酸化AKT）增强卵巢癌细胞细胞糖酵解途径中的作用。PITX2的表达与高级别浆液性卵巢癌组织和普通卵巢癌细胞系中限速酶乳酸脱氢酶-A（LDHA）的糖酸峰值相正相关。有趣的是，观察到在PITX2过量表达的卵巢癌细胞中，酶活性LDHA的短暂局部化在细胞核中。该核内LDHA生产更高浓度的糖酸末端产物乳酸，乳酸在核区域积累，导致减少组蛋白脱乙酰化酶（HDAC1/2）表达和增加位点H3/H4的组蛋白乙酰化。然而，乳酸-HDAC相互作用的机械细节在早期报告中仍然模糊。我们的体外研究通过配体结合研究和分子动力学模拟方法详细说明了乳酸在HDAC催化核心中的相互作用动力学。通过沉默LDHA阻断乳酸的产生可以减少癌细胞增殖。因此，PITX2诱导的表观遗传变化可能导致高细胞增殖和增大在同基因小鼠中的肿瘤大小。综上所述，这是首次报道表明发育调节Homeobox基因PITX2通过增强肿瘤细胞的糖酵解而引起表观遗传修饰，从而增强肿瘤学的产生。©2023 Wiley Periodicals LLC。

Homeobox gene families are associated with embryonic development and organogenesis. Pieces of evidence suggest that these Homeobox genes are also crucial in facilitating oncogenesis when mutated or overexpressed. Paired homeodomain transcription factor-2 (PITX2), one of the members of this family, is involved in oncogenic regulation apart from its different development regulatory functions. PITX2 has been earlier shown to induce ovarian cancer cell proliferation through the activation of different signaling cascades. Increased cancer cell proliferation requires a constant supply of nutrients for both adenosine triphosphate and biomass synthesis, which is facilitated by altered cancer cell metabolism that includes enhanced glucose uptake and increased glycolytic rate. This present study highlights the involvement of PITX2 in enhancing the cellular glycolysis pathway in ovarian cancer cells through protein kinase B-phosphorylation (phospho-AKT). PITX2 expression correlates positively with that of the glycolytic rate-determining enzyme, lactate dehydrogenase-A (LDHA), in both high-grade serous ovarian cancer tissues and common ovarian cancer cell lines. Interestingly, transient localization of enzymatically active LDHA in the nucleus was observed in PITX2-overexpressed ovarian cancer cells. This nuclear LDHA produces higher concentrations of the glycolytic end product, lactate, which accumulates in the nuclear compartment resulting in decreased histone deacetylase (HDAC1/2) expression and increased histone acetylation at H3/H4. However, the mechanistic details of lactate-HDAC interaction are still elusive in the earlier reports. Our in silico studies elaborated on the interaction dynamics of lactate in the HDAC catalytic core through ligand-binding studies and molecular dynamics simulation approaches. Blocking lactate production by silencing LDHA reduced cancer cell proliferation. Thus, PITX2-induced epigenetic changes can lead to high cellular proliferation and increase the size of tumors in syngeneic mice as well. Taken together, this is the first report of its kind to show that the developmental regulatory homeobox gene PITX2 could enhance oncogenesis through enhanced glycolysis of tumor cells followed by epigenetic modifications.© 2023 Wiley Periodicals LLC.