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BHLHE40-PPM1F-AMPK 通路调节能量代谢，并与子宫内膜癌的侵袭性相关。

The BHLHE40‒PPM1F‒AMPK pathway regulates energy metabolism and is associated with the aggressiveness of endometrial cancer.

机构信息

Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

出版信息

J Biol Chem. 2024 Mar;300(3):105695. doi: 10.1016/j.jbc.2024.105695. Epub 2024 Jan 30.

DOI:10.1016/j.jbc.2024.105695
PMID:38301894
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10904277/
Abstract

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.

摘要

BHLHE40 是一种基本螺旋-环-螺旋转录因子，参与多种细胞活动，包括分化、细胞周期和上皮-间充质转化。虽然有越来越多的证据支持 BHLHE40 在能量代谢中的功能，但对其机制知之甚少。在这项研究中，我们发现 BHLHE40 的表达在高级别和晚期子宫内膜癌病例中下调。在子宫内膜癌细胞中敲低 BHLHE40 导致耗氧量降低和细胞外酸化增强。在敲低的细胞中观察到丙酮酸脱氢酶（PDH）活性受抑制和乳酸脱氢酶（LDH）活性增强。BHLHE40 的敲低还导致 AMPKα Thr172 去磷酸化，并增强丙酮酸脱氢酶 E1 亚基α 1（PDHA1）Ser293 和乳酸脱氢酶 A（LDHA）Tyr10 的磷酸化。这些结果表明，BHLHE40 通过调节 PDHA1 和 LDHA 的磷酸化状态来调节 PDH 和 LDH 的活性。我们发现 BHLHE40 通过直接抑制 AMPKα 特异性磷酸酶 PPM1F 的转录来增强 AMPKα 的磷酸化。我们的免疫组织化学研究表明，BHLHE40、PPM1F 和磷酸化 AMPKα 的表达与子宫内膜癌患者的预后相关。因为 AMPK 是癌细胞能量代谢的中央调节剂，靶向 BHLHE40-PPM1F-AMPK 轴可能代表控制癌症发展的一种策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/8a8f2bd06cf8/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/7aa44431aae2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/e3752002a116/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/962959fcc009/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/47568601bfcb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/15b259783bf5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/edb5a1b03a9f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/998122760a3b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/8a8f2bd06cf8/gr8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/7aa44431aae2/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/e3752002a116/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/962959fcc009/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/47568601bfcb/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/15b259783bf5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/edb5a1b03a9f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/998122760a3b/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/055a/10904277/8a8f2bd06cf8/gr8.jpg

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