Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor-resistant pancreatic ductal adenocarcinoma.
Transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor-resistant pancreatic ductal adenocarcinoma.
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DOI：
10.3389/fonc.2022.926437
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发表时间：
2022
影响因子：
4.7
通讯作者：
Wajapeyee, Narendra
中科院分区：
文献类型：
--
作者：
Malvi, Parmanand;Rawat, Vipin;Gupta, Romi;Wajapeyee, Narendra
部分由于代谢酶的过度表达，代谢重编程是癌细胞的关键标志。乳酸脱氢酶（LDHA）是一种催化乳酸和丙酮酸相互转化的代谢酶，在多种癌症类型中过表达，包括胰腺导管腺癌（PDAC）。此外，LDHA的遗传或药理学抑制可抑制癌症生长，证明这种酶具有促癌作用。因此，正在开发和测试几种药理学LDHA抑制剂作为潜在的抗癌治疗剂。由于已知癌细胞快速适应并对抗癌疗法产生抗性，因此在本研究中，我们模拟了癌细胞对LDHA抑制的适应。使用PDAC作为模型系统，我们研究了细胞对竞争性LDHA抑制剂草氨酸钠的抗性的分子方面。我们进行了无偏RNA测序（RNA-seq），转座酶可接近染色质测序（ATAC-seq），和代谢组学分析的亲本和草酸盐耐药PDAC细胞与草酸盐处理和不处理，以确定这些细胞的转录，染色质和代谢景观。我们发现，草酸酯耐药PDAC细胞在mRNA表达水平，染色质可及性和代谢产物方面与亲本细胞有显著差异。此外，结合RNA-seq和ATAC-seq数据集的综合分析确定了与染色质可及性变化直接相关的差异表达mRNA的子集。最后，在用和不用草氨酸盐处理的亲本和草氨酸盐抗性PDAC细胞中差异表达的代谢基因的功能分析，以及RNA-seq和代谢组学数据的综合分析，揭示了代谢酶的变化，这可能解释在这些细胞中观察到的代谢物水平的变化。总的来说，这些研究确定了PDAC细胞中LDHA抑制剂抗性的转录、染色质和代谢景观。与这些变化相关的未来功能研究仍然有必要揭示这些变化在LDHA抑制剂耐药性发展中所起的直接作用，并揭示在癌症治疗中更有效地使用LDHA抑制剂的方法。
Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.
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影响因子：
--
作者：
Rong, Yefei;Wu, Wenchuan;Lou, Wenhui
通讯作者：
Lou, Wenhui
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
10.6
作者：
Cheng CS;Tan HY;Wang N;Chen L;Meng Z;Chen Z;Feng Y
通讯作者：
Feng Y
DOI：
10.1073/pnas.1501605112
发表时间：
2015-08-11
影响因子：
11.1
作者：
Daemen, Anneleen;Peterson, David;Evangelista, Marie
通讯作者：
Evangelista, Marie
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.