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NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression

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机构： [1]Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, 550001 Guiyang, China [2]Department of Clinical Medicine, Guizhou MedicalUniversity, 550001 Guiyang, Guizhou, China [3]Breast and Thyroid Disease Center, The Third People’s Hospital of Chengdu, Sichuan, China [4]Department of Pathophysiology,School of Basic Medical Sciences, Guizhou Medical University, 550025 Guiyang, Guizhou, China [5]Department of Physiology, School of Basic Medical Sciences, Guizhou MedicalUniversity, 550025 Guiyang, China [6]Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, 550025 Guiyang,China [7]Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, China [8]AffiliatedHospital of Guizhou Medical University, 550001 Guiyang, China [9]Precision Medicine Research Institute of Guizhou, The Affiliated Hospital of Guizhou Medical University, 550001Guiyang, China

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We have previously shown that nucleosome assembly protein 1-like 1 (NAP1L1) plays an important role in the abnormal proliferation of hepatocellular carcinoma (HCC) cells. However, the effects of NAP1L1 on the malignant behaviour of HCC cells, including cell migration, invasion and apoptosis, remain unclear. Baculoviral IAP repeat-containing 2 (BIRC2) plays a key role in initiating the abnormal proliferation, apoptotic escape and multidrug resistance of HCC cells; however, the mechanisms through which its stability is regulated in HCC remain elusive. Here, we found that knockdown of NAP1L1 inhibited the proliferation of HCC cells and activated apoptotic pathways but did not remarkably affect the migratory and invasive abilities of HCC cells. In addition, knockdown of NAP1L1 did not alter the expression of BIRC2 at the transcriptional level but substantially reduced its expression at the translational level, suggesting that NAP1L1 is involved in the post-translational modification (such as ubiquitination) of BIRC2. Furthermore, BIRC2 was highly expressed in human HCC tissues and promoted the proliferation and apoptotic escape of HCC cells. Co-immunoprecipitation (Co-IP) assay and mass spectrometry revealed that NAP1L1 and BIRC2 did not bind to each other; however, ubiquitin protein ligase E3 component n-recognin 4 (UBR4) was identified as an intermediate molecule associating NAP1L1 with BIRC2. Knockdown of NAP1L1 promoted the ubiquitin-mediated degradation of BIRC2 through the ubiquitin-protein junction of UBR4, which in turn inhibited the proliferation and apoptotic escape of HCC cells and exerted anti-tumour effects. In conclusion, this study reveals a novel mechanism through which NAP1L1 regulates the ubiquitination of BIRC2 through UBR4, thereby determining the progression of HCC. Based on this mechanism, suppression of NAP1L1 may inhibit tumour progression in patients with HCC with high protein expression of NAP1L1 or BIRC2.© 2024. The Author(s).

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大类 | 2 区生物学

小类 | 2 区细胞生物学

第一作者：

第一作者机构： [1]Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, 550001 Guiyang, China [2]Department of Clinical Medicine, Guizhou MedicalUniversity, 550001 Guiyang, Guizhou, China [3]Breast and Thyroid Disease Center, The Third People’s Hospital of Chengdu, Sichuan, China

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通讯机构： [1]Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, 550001 Guiyang, China [5]Department of Physiology, School of Basic Medical Sciences, Guizhou MedicalUniversity, 550025 Guiyang, China [6]Transformation Engineering Research Center of Chronic Disease Diagnosis and Treatment, Guizhou Medical University, 550025 Guiyang,China [7]Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, 550025 Guiyang, China [8]AffiliatedHospital of Guizhou Medical University, 550001 Guiyang, China [9]Precision Medicine Research Institute of Guizhou, The Affiliated Hospital of Guizhou Medical University, 550001Guiyang, China

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