p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells.
p53-inducible DPYSL4 associates with mitochondrial supercomplexes and regulates energy metabolism in adipocytes and cancer cells.
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DOI：
10.1073/pnas.1804243115
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发表时间：
2018-08-14
影响因子：
11.1
通讯作者：
Tanaka T
中科院分区：
文献类型：
--
作者：
Nagano H;Hashimoto N;Nakayama A;Suzuki S;Miyabayashi Y;Yamato A;Higuchi S;Fujimoto M;Sakuma I;Beppu M;Yokoyama M;Suzuki Y;Sugano S;Ikeda K;Tatsuno I;Manabe I;Yokote K;Inoue S;Tanaka T
我们在此进行RNA测序以显示DPYSL 4是癌细胞和正常细胞（例如脂肪细胞）中的能量代谢的p53诱导型调节剂。DPYSL 4被发现定位于细胞质和线粒体中，特别是与线粒体超复合物相关，为其调节OXPHOS和细胞能量供应提供了潜在的机制。此外，DPYSL 4表达抑制体内肿瘤生长和转移。总之，这些结果表明p53诱导的DPYSL 4与癌症和代谢紊乱的病理生理学之间存在潜在联系，可能通过其能量调节功能。肿瘤抑制因子p53调节多种细胞功能，包括能量代谢。代谢失调与某些癌症的发病机制和代谢紊乱有关，可能是由于p53功能失活所致。利用癌细胞和前脂肪细胞的RNA测序和ChIP测序，我们证明了p53通过反式激活包括二氢嘧啶酶样4（DPYSL 4）在内的能量代谢基因来调节几种代谢过程。DPYSL 4是参与癌症侵袭和进展的胰蛋白酶应答介导蛋白家族的成员。有趣的是，DPYSL 4在癌细胞和前脂肪细胞中的过表达上调了ATP的产生和氧消耗，而使用siRNA或CRISPR/Cas9敲低DPYSL 4则下调了能量的产生。此外，DPYSL 4与线粒体超复合物相关，其二氢嘧啶酶样结构域的缺失消除了其相关性及其刺激ATP产生和抑制癌细胞侵袭的能力。小鼠异种移植和肺转移模型表明，DPYSL 4表达损害体内肿瘤生长和转移。一致地，数据库分析表明，低DPYSL 4表达与乳腺癌和卵巢癌的不良存活率显著相关，这与其在某些类型的癌组织中的表达降低一致。此外，使用肥胖患者脂肪组织的免疫组织化学分析显示，DPYSL 4表达与INFg和体重指数呈正相关，与p53激活一致。总之，这些结果表明，DPYSL 4通过调节氧化磷酸化和细胞能量供应，通过其与线粒体超复合物的关联，在p53的肿瘤抑制功能中起着关键作用，可能与癌症和肥胖的病理生理学有关。
We herein performed RNA sequencing to show that DPYSL4 is a p53-inducible regulator of energy metabolism in both cancer cells and normal cells, such as adipocytes. DPYSL4 was found to localize in both cytosol and mitochondria, particularly in associations with mitochondrial supercomplexes, providing a potential mechanism for its regulation of OXPHOS and cellular energy supply. Furthermore, DPYSL4 expression suppressed tumor growth and metastasis in vivo. Together, these results suggest a potential link between p53-inducible DPYSL4 and the pathophysiology of cancer and metabolic disorders, possibly via its energy-regulating function. The tumor suppressor p53 regulates multiple cellular functions, including energy metabolism. Metabolic deregulation is implicated in the pathogenesis of some cancers and in metabolic disorders and may result from the inactivation of p53 functions. Using RNA sequencing and ChIP sequencing of cancer cells and preadipocytes, we demonstrate that p53 modulates several metabolic processes via the transactivation of energy metabolism genes including dihydropyrimidinase-like 4 (DPYSL4). DPYSL4 is a member of the collapsin response mediator protein family, which is involved in cancer invasion and progression. Intriguingly, DPYSL4 overexpression in cancer cells and preadipocytes up-regulated ATP production and oxygen consumption, while DPYSL4 knockdown using siRNA or CRISPR/Cas9 down-regulated energy production. Furthermore, DPYSL4 was associated with mitochondrial supercomplexes, and deletion of its dihydropyrimidinase-like domain abolished its association and its ability to stimulate ATP production and suppress the cancer cell invasion. Mouse-xenograft and lung-metastasis models indicated that DPYSL4 expression compromised tumor growth and metastasis in vivo. Consistently, database analyses demonstrated that low DPYSL4 expression was significantly associated with poor survival of breast and ovarian cancers in accordance with its reduced expression in certain types of cancer tissues. Moreover, immunohistochemical analysis using the adipose tissue of obese patients revealed that DPYSL4 expression was positively correlated with INFg and body mass index in accordance with p53 activation. Together, these results suggest that DPYSL4 plays a key role in the tumor-suppressor function of p53 by regulating oxidative phosphorylation and the cellular energy supply via its association with mitochondrial supercomplexes, possibly linking to the pathophysiology of both cancer and obesity.
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影响因子：
30.8
作者：
Bourdon, Alice;Minai, Limor;Rotig, Agnes
通讯作者：
Rotig, Agnes
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Singh KK
影响因子：
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作者：
Lebedeva, Maria A.;Eaton, Jana S.;Shadel, Gerald S.
通讯作者：
Shadel, Gerald S.