ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2
ABHD5 interacts with BECN1 to regulate autophagy and tumorigenesis of colon cancer independent of PNPLA2
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ABHD5 与 BECN1 相互作用，独立于 PNPLA2 调节结肠癌的自噬和肿瘤发生
DOI：
10.1080/15548627.2016.1217380
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Ou, Juanjuan
中科院分区：
文献类型：
--
作者：
Peng, Yuan;Miao, Hongming;Ou, Juanjuan
摘要自噬对代谢重编程和染色体稳定性有重要作用。据报道，必需的自噬基因BECN 1（编码BECN 1/Beclin 1）的单等位基因缺失促进癌症的发展和进展。然而，BECN 1在恶性肿瘤中失活的机制在很大程度上仍然难以捉摸。我们以前曾报道ABHD 5（abhydrolase domain containing 5），PNPLA 2（patatin like phospholipase domain containing 2）的共激活剂在结直肠癌（CRC）中的肿瘤抑制作用。在这里，我们报告了ABHD 5在调节自噬和CRC肿瘤发生中的非经典作用。ABHD 5直接与CASP 3竞争结合BECN 1的切割位点，从而阻止BECN 1被CASP 3切割。ABHD 5缺陷为CASP 3提供了切割和抑制BECN 1的优势，从而削弱了BECN 1诱导的自噬通量并增加了基因组不稳定性，这随后促进了肿瘤发生。值得注意的是，临床数据还证实ABHD 5熟练度与人CRC组织中BECN 1、LC 3-II和CASP 3的表达水平显著相关。我们的研究结果表明，ABHD 5在调节自噬和肿瘤发生方面具有PNPLA 2独立的功能，进一步确立了ABHD 5的肿瘤抑制作用，并为开发旨在预防CRC致癌的新方法提供了机会。
ABSTRACT Autophagy critically contributes to metabolic reprogramming and chromosomal stability. It has been reported that monoallelic loss of the essential autophagy gene BECN1 (encoding BECN1/Beclin 1) promotes cancer development and progression. However, the mechanism by which BECN1 is inactivated in malignancy remains largely elusive. We have previously reported a tumor suppressor role of ABHD5 (abhydrolase domain containing 5), a co-activator of PNPLA2 (patatin like phospholipase domain containing 2) in colorectal carcinoma (CRC). Here we report a noncanonical role of ABHD5 in regulating autophagy and CRC tumorigenesis. ABHD5 directly competes with CASP3 for binding to the cleavage sites of BECN1, and consequently prevents BECN1 from being cleaved by CASP3. ABHD5 deficiency provides CASP3 an advantage to cleave and inactivate BECN1, thus impairing BECN1-induced autophagic flux and augmenting genomic instability, which subsequently promotes tumorigenesis. Notably, clinical data also confirm that ABHD5 proficiency is significantly correlated with the expression levels of BECN1, LC3-II and CASP3 in human CRC tissues. Our findings suggest that ABHD5 possesses a PNPLA2-independent function in regulating autophagy and tumorigenesis, further establishing the tumor suppressor role of ABHD5, and offering an opportunity to develop new approaches aimed at preventing CRC carcinogenesis.