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PRMT7: a survive-or-die switch in cancer stem cells
Molecular Cancer ( IF 27.7 ) Pub Date : 2022-06-10 , DOI: 10.1186/s12943-022-01602-z
Christophe Nicot 1
Affiliation  

Cancer stem-like cells (CSCs) are involved in initiation, resistance and relapse of cancer [1, 2]. Identifying targets uniquely expressed in CSCs, instead their normal counterparts, has been puzzling the field of cancer biology. In the quintessential paradigm of CSCs in chronic myeloid leukemia (CML), resistance at least partially conferred by leukemia stem cells (LSCs) remains an increasing threat in patients diagnosed with CML [3, 4] despite tyrosine kinase inhibitors such as Imatinib mesylate magically prolonging the survival and improving life quality. In a recent issue of Cell Metabolism, Liu et al. [5] have demonstrated that protein arginine methyltransferase 7 (PRMT7) get hold of a survive-or-die switch in CML LSCs. Indeed, targeting PRMT7 by either genetic or pharmacological approaches selectively eliminate LSCs while sparing normal counterpart cells. The mechanism has been well illustrated. These findings have brought us a phenomenal therapeutic target for CSCs.

Epigenetics provide rooms for recognizing the intricate regulation of stemness [6,7,8]. In their studies, Liu et al. [5] chose PRMT7 based on differential expression in CML LSCs, and authors took advantages of genetic and pharmacological tactics to comprehensively characterize the function of PRMT7 in survival and self-renewal of CML LSCs. First, they generated hematopoietic cell-specific Prmt7 knockout mice to investigate the role of Prmt7 in leukemogenesis of BCR-ABL-driven CML. Interestingly, the authors found that conditional knockout (CKO) of Prmt7 markedly delayed the development of leukemia, and significantly mitigated leukemia burden in CML mice. Of note, Prmt7 CKO dramatically reduced the populations of leukemia stem/progenitor cells (LSPCs) and the frequency of LSCs. Prmt7 CKO also suppressed the CFC/replating capacity of LSCs and the disease reconstitution ability of LSCs in secondary recipients. These lines of compelling evidence indicate that PRMT7 is required for the self-renewal of LSCs. In the meantime, Prmt7 CKO did not impact either the frequency of hematopoietic stem cells (HSCs), or their function of normal HSCs.

After obtaining evidence that PRMT7 regulates LSCs in a methyltransferase catalysis-dependent manner, the authors set out to develop small molecule inhibitors against PRMT7. Authors successfully synthesized a small inhibitor, JS1310, which selectivity inhibited PRMT7 but not other PRMT family members. In vivo studies using JS1310 treatment prominently eliminated LSCs and prolonged survival of CML mice. Most importantly, authors also investigated the effects of JS1310 on primary CD34+ cells from CML patients or healthy donors. JS1310 profoundly suppressed the survival and self-renewal ability of CML CD34+ cells without affecting normal CD34+ cells. In a patient-derived xenograft model, JS1310 treatment showed a significant inhibition in the long-term engraftment capacity of human CML CD34+ cells. Overall, PRMT7 may represent a unique and valuable therapeutic target against CML LSCs.

To gain insight into the underlying mechanism, the authors did RNA-seq analysis and found that glycine decarboxylase (GLDC) [9, 10], a rate-limiting enzyme in glycine metabolism regulation network, was significantly downregulated in Prmt7-CKO LSCs compared to wild-type counterparts. Rescue experiments revealed that GLDC regulated LSCs in an enzyme activity-dependent manner. Furthermore, ChIP assay showed that the symmetric methylation of H2AR3 by PRMT7 decreased the enrichment of TRPS1 at the promoter region of GLDC, suggesting that transcriptional repressor GATA binding 1 (TRPS1) may be a mediator for PRMT7 to regulate GLDC. Surprisingly, PRMT7 CKO did not alter TRPS1 and GLDC expression in normal HSCs. This may provide a well and helpful explanation for the phenotype that loss of PRMT7 is not detrimental to normal HSCs.

Gene Ontology analysis revealed that genes related glycine and serine metabolism pathway were significantly enriched in the Prmt7 CKO LSCs. High pressure-liquid chromatography-mass spectrometry analysis indicated a progressive increase in intracellular glycine and serine with progression of CML disease in CML mice. Besides, loss of PRMT7 resulted in excessive accumulation of glycine in LSCs.

Glycine generated from serine by serine hydroxymethyltransferase 2 (SHMT2) can be converted to either non-toxic 5, 10-methylene-tetrahydrofolate (5, 10-MTHF) by GLDC or toxic methylglyoxal by glycine C-acetyltransferase (GCAT) [11, 12]. The authors hypothesized that the increased apoptosis in LSCs might be implemented by toxic methylglyoxal which is converted from excess glycine in Prmt7-CKO LSCs. As expected, methylglyoxal level was remarkably increased in Prmt7-CKO LSCs from CML mice or PRMT7 inhibitor-treated CD34+ cells from patients with CML. Methylglyoxal treatment indeed suppressed survival and self-renewal of LSCs. Prmt7-CKO CML mice fed with serine and glycine-free (SG-free) diet exhibited shorted survival than those fed with control diet. SG-free diet also reversed the Prmt7 CKO-mediated decrease in leukemia cells and LSPCs.

Taken together, the authors proposed the working model (Fig. 1). In the context of intact PRMT7 overexpressed in LSCs, glycine metabolism affluently provides 5, 10-MTHF allowing LSCs metabolic addiction. In the context of PRMT7 deletion or inhibition, however, not only the pro-survival of metabolic addiction was blocked but also the glycine metabolism is reshaped to generate excessive methylglyoxal, which is poisonous to LSCs. In the case of normal HSCs absent of PRMT7 overexpression, inhibition of PRMT7 would not kill normal HSCs because of lack of the target. These findings have underscored that PRMT7 is a promisingly selective target of LSCs, and greatly improved our understanding on epigenetic regulation of CSCs. However, relevant question like how PRMT7 is overexpressed in CML LSCs remain to be addressed in future.

Fig. 1
figure 1

PRMT7 seizes glycine metabolism switch to determine fate of LSCs. A PRMT7 catalyzes H2AR3me2s to inhibit the transcription repressor of TRPS1, eventually upregulating GLDC in CML LSCs. Glycine generated from serine by SHMT2 is converted by GLDC to 5, 10-MTHF, allowing LSCs to gain metabolic addiction. B Genetic deletion or pharmacological inhibition of PRMT7 derepresses the repressor TRPS1, thereby downregulates GLDC and subsequently accumulates intracellular glycine in CML LSCs. Increased intracellular glycine is converted by GCAT to methylglyoxal, which induces the death of CML LSCs

Full size image

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Authors and Affiliations

  1. Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

    Christophe Nicot

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CN wrote the commentary. The author(s) read and approved the final manuscript.

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Correspondence to Christophe Nicot.

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The author declares no financial conflict of interest. Christophe Nicot is Editor-in-Chief of Molecular Cancer.

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Nicot, C. PRMT7: a survive-or-die switch in cancer stem cells. Mol Cancer 21, 127 (2022). https://doi.org/10.1186/s12943-022-01602-z

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中文翻译：
PRMT7：癌症干细胞中的生存或死亡开关

癌症干细胞样细胞 (CSC) 参与癌症的发生、抵抗和复发 [1, 2]。识别在 CSC 中唯一表达的靶标，而不是它们的正常对应物，一直困扰着癌症生物学领域。在慢性髓性白血病 (CML) 中 CSCs 的典型范例中，至少部分由白血病干细胞 (LSCs) 赋予的耐药性仍然对诊断为 CML 的患者构成越来越大的威胁 [3, 4] 尽管甲磺酸伊马替尼等酪氨酸激酶抑制剂神奇地延长生存和提高生活质量。在最近一期的细胞代谢, 刘等人。[5] 已经证明蛋白质精氨酸甲基转移酶 7 (PRMT7) 在 CML LSC 中控制了生存或死亡开关。事实上，通过遗传或药理学方法靶向 PRMT7 可以选择性地消除 LSC，同时保留正常的对应细胞。该机制已得到很好的说明。这些发现为我们带来了一个非凡的 CSC 治疗靶点。

表观遗传学为识别干性的复杂调节提供了空间[6,7,8]。在他们的研究中，刘等人。[5]基于CML LSCs的差异表达选择PRMT7，并利用遗传和药理策略，全面表征PRMT7在CML LSCs生存和自我更新中的功能。首先，他们生成了造血细胞特异性Prmt7敲除小鼠，以研究Prmt7在 BCR-ABL 驱动的 CML 白血病发生中的作用。有趣的是，作者发现Prmt7的条件性敲除 (CKO)显着延缓了白血病的发展，并显着减轻了 CML 小鼠的白血病负担。值得注意的是，Prmt7CKO 显着减少了白血病干/祖细胞 (LSPC) 的数量和 LSC 的频率。Prmt7 CKO 还抑制了 LSCs 的 CFC/replating 能力和 LSCs 在二级受体中的疾病重建能力。这些令人信服的证据表明 PRMT7 是 LSC 自我更新所必需的。同时，Prmt7 CKO 既不影响造血干细胞 (HSC) 的频率，也不影响其正常 HSC 的功能。

在获得 PRMT7 以甲基转移酶催化依赖性方式调节 LSC 的证据后，作者着手开发针对 PRMT7 的小分子抑制剂。作者成功合成了一种小型抑制剂 JS1310，它选择性抑制 PRMT7，但不抑制其他 PRMT 家族成员。使用 JS1310 治疗的体内研究显着消除了 LSC，并延长了 CML 小鼠的存活期。最重要的是，作者还研究了 JS1310 对 CML 患者或健康供体的原代 CD34 +细胞的影响。JS1310在不影响正常CD34 +的情况下，深度抑制CML CD34 +细胞的存活和自我更新能力细胞。在患者来源的异种移植模型中，JS1310 治疗显示出对人 CML CD34 +细胞的长期移植能力的显着抑制。总体而言，PRMT7 可能代表针对 CML LSCs 的独特且有价值的治疗靶点。

为了深入了解潜在机制，作者进行了 RNA-seq 分析，发现甘氨酸脱羧酶 (GLDC) [9, 10]，一种甘氨酸代谢调节网络中的限速酶，在Prmt7中显着下调-CKO LSCs 与野生型对应物相比。救援实验表明 GLDC 以酶活性依赖性方式调节 LSC。此外，ChIP 分析表明 PRMT7 对 H2AR3 的对称甲基化降低了 TRPS1 在 GLDC 启动子区域的富集，这表明转录抑制因子 GATA 结合 1 (TRPS1) 可能是 PRMT7 调节 GLDC 的介质。令人惊讶的是，PRMT7 CKO 并未改变正常 HSC 中的 TRPS1 和 GLDC 表达。这可能为 PRMT7 的缺失对正常 HSC 无害的表型提供了一个很好且有用的解释。

基因本体分析显示，与甘氨酸和丝氨酸代谢途径相关的基因在Prmt7 CKO LSCs 中显着富集。高压-液相色谱-质谱分析表明，随着 CML 小鼠 CML 疾病的进展，细胞内甘氨酸和丝氨酸逐渐增加。此外，PRMT7 的丢失导致 LSC 中甘氨酸的过度积累。

由丝氨酸羟甲基转移酶 2 (SHMT2) 从丝氨酸生成的甘氨酸可通过 GLDC 转化为无毒的 5, 10-亚甲基四氢叶酸 (5, 10-MTHF)，或通过甘氨酸 C-乙酰转移酶 (GCAT) 转化为有毒的甲基乙二醛 [11, 12 ]。作者假设 LSCs 细胞凋亡的增加可能是由有毒的甲基乙二醛实现的，该甲基乙二醛是从Prmt7 -CKO LSCs 中过量的甘氨酸转化而来的。正如预期的那样，来自 CML 小鼠的Prmt7 -CKO LSC 或来自 CML 患者的 PRMT7 抑制剂处理的 CD34 +细胞中的甲基乙二醛水平显着增加。甲基乙二醛治疗确实抑制了 LSC 的存活和自我更新。prmt7-CKO CML 小鼠喂食无丝氨酸和甘氨酸（无 SG）饮食的存活期比喂食对照饮食的小鼠短。无 SG 饮食也逆转了Prmt7 CKO 介导的白血病细胞和 LSPC 的减少。

综上所述，作者提出了工作模型（图 1）。在 LSCs 中过表达的完整 PRMT7 的情况下，甘氨酸代谢丰富地提供 5, 10-MTHF 允许 LSCs 代谢成瘾。然而，在 PRMT7 缺失或抑制的情况下，不仅代谢成瘾的促生存被阻断，而且甘氨酸代谢被重塑以产生过量的甲基乙二醛，这对 LSC 有毒。在没有 PRMT7 过表达的正常 HSC 的情况下，由于缺乏靶标，抑制 PRMT7 不会杀死正常 HSC。这些发现强调了 PRMT7 是 LSCs 的一个有希望的选择性靶标，并极大地提高了我们对 CSCs 表观遗传调控的理解。然而，诸如 PRMT7 如何在 CML LSC 中过度表达等相关问题仍有待解决。

图。1
图1

PRMT7 抓住甘氨酸代谢开关来决定 LSCs 的命运。PRMT7催化 H2AR3me2s 抑制 TRPS1 的转录阻遏物，最终上调 CML LSCs 中的 GLDC。SHMT2 由丝氨酸产生的甘氨酸被 GLDC 转化为 5, 10-MTHF，使 LSC 获得代谢成瘾。B PRMT7 的基因缺失或药理学抑制去抑制阻遏物 TRPS1，从而下调 GLDC 并随后在 CML LSCs 中积累细胞内甘氨酸。GCAT 将增加的细胞内甘氨酸转化为甲基乙二醛，从而诱导 CML LSCs 死亡

全尺寸图片

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Nicot, C. PRMT7：癌症干细胞中的生存或死亡开关。摩尔癌症 21, 127 (2022)。https://doi.org/10.1186/s12943-022-01602-z

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