Department of Immunology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea.
R&D Center, CHA Vaccine Institute, Seongnam-si, 13493, Republic of Korea.
Cell Death Dis. 2022 Apr 14;13(4):348. doi: 10.1038/s41419-022-04808-7.
TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.
肿瘤坏死因子受体相关因子 6（TRAF6）-BECN1 信号轴通过 BECN1 的泛素化在自噬诱导中发挥关键作用，从而诱导肺癌迁移和侵袭以响应 Toll 样受体 4（TLR4）刺激。在此，我们提供了涉及泛素特异性肽酶 15（USP15）对肺癌进展的负向影响的新的分子和细胞机制。TCGA 和原发性非小细胞肺癌（NSCLC）患者的临床数据（n=41）显示，USP15 在肺癌患者中的表达明显下调。重要的是，使用 CRISPR-Cas9 基因编辑技术生成的 USP15 敲除（USP15KO）A549 和 USP15KO H1299 肺癌细胞在 TLR4 刺激下表现出增加的癌症迁移和侵袭，同时增强了自噬诱导。此外，生化研究表明，USP15 与 BECN1 相互作用，而不是与 TRAF6 相互作用，并诱导 BECN1 的去泛素化，从而减弱自噬诱导。值得注意的是，在 USP15 低表达的 4 名原发性 NSCLC 患者（n=4）中，已知促进肺癌进展的 10 个基因（CCNE1、MMP9、SFN、UBE2C、CCR2、FAM83A、ETV4、MYO7A、MMP11 和 GSDMB）显著上调，而 10 个肿瘤抑制基因（FMO2、ZBTB16、FCN3、TCF21、SFTPA1B、HPGD、SOSTDC1、TMEM100、GDF10 和 WIF1）下调，为 USP15 在肺癌进展中的功能作用提供了临床相关性。总之，我们的数据表明 USP15 可以负调控 TRAF6-BECN1 信号轴以诱导自噬。因此，USP15 参与了肺癌的进展。
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