N-Myc transcriptionally activates Skp2 to suppress p27 expression in small cell lung cancer

Juntao Zou; Yang Lin; Min Hu; Mengzhi Wan; Xinyu Tan; Xinping Xu; Fei Xu

doi:10.1016/j.prp.2022.154083

N-Myc transcriptionally activates Skp2 to suppress p27 expression in small cell lung cancer

Pathol Res Pract. 2022 Oct:238:154083. doi: 10.1016/j.prp.2022.154083. Epub 2022 Aug 22.

Authors

Juntao Zou¹, Yang Lin¹, Min Hu¹, Mengzhi Wan¹, Xinyu Tan¹, Xinping Xu², Fei Xu³

Affiliations

¹ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Dongxin Township, Nanchang County, Nanchang 330006, Jiangxi, China.
² Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Dongxin Township, Nanchang County, Nanchang 330006, Jiangxi, China. Electronic address: xinpingxu@ncu.edu.cn.
³ Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 1519, Dongyue Avenue, Dongxin Township, Nanchang County, Nanchang 330006, Jiangxi, China. Electronic address: xfjxmc@163.com.

PMID: 36027654
DOI: 10.1016/j.prp.2022.154083

Abstract

Background: Small cell lung cancer (SCLC) is characterized by a high proliferative rate, a strong predilection for early metastasis and poor prognosis. Novel SCLC biomarkers are urgently required to improve current diagnostic and treatment modalities. MYCN encodes the proto-oncogene N-Myc that is overexpressed in SCLC, but its downstream effectors are poorly characterized. Here, we investigated the role of the N-Myc/Skp2/p27 axis during SCLC progression.

Methods: Immunohistochemistry (IHC) and western blotting were performed to evaluate N-Myc/Skp2/p27 expression. SCLC cell apoptosis was investigated through TUNEL staining. Wound healing and transwell assays were performed to detect the migratory and invasive potential of SCLC cells. N-Myc and Skp2 binding was confirmed through luciferase reporter and ChIP assays. Xenograft models were developed to investigate the function of Skp2 during SCLC tumor growth in vivo.

Results: N-Myc and Skp2 were overexpressed in SCLC, whilst p27 expression was suppressed. Skp2 facilitated SCLC progression by protecting cells from apoptosis and facilitating cell migration and invasion. N-Myc was found to bind to the promoter region of Skp2 to enhance its expression. Skp2 enhanced tumor growth in vivo through the suppression of p27. Skp2 silencing reversed the pro-oncogenic effects of N-myc in SCLC tumors.

Conclusion: We show that N-Myc enhances Skp2 to regulate p27 expression during SCLC progression. We therefore highlight the N-Myc/Skp2/p27 axis as a novel diagnostic and much-needed therapeutic target in SCLC.

Keywords: N-Myc; P27; Skp2; Small cell lung cancer.