Lung cancer (LC), a malignant tumor originating from the lung tissue, is one of the cancers with the highest morbidity and mortality worldwide [1,2]. One of the reasons why LC ranks at the top is that it is often diagnosed at an advanced stage and has a poor prognosis [3,4]. According to statistics, the number of new cases and deaths from LC each year is 2.5 million and 1.8 million, respectively [5]. Although constantly updating the diagnosis and treatment, the survival rate of LC patients is still unsatisfactory, only 18% [1,6]. Therefore, exploring the pathogenesis and the novel diagnostic and therapeutic targets of LC are of great significance [7].

The complex molecular pathogenesis of LC involves dysregulation of numerous cellular processes, among which post-translational modifications, particularly ubiquitination and its reversal by deubiquitinases (DUBs), have become key regulatory mechanisms [8,9]. Cylindromatosis (CYLD), a DUB, is initially discovered as a mutated tumor suppressor in familiar cylindromatosis [10], and it inhibits the NF-κB and JNK pathways by removing the lysine-63 combined ubiquitin chain from specific substrates [11,12]. It had been reported that CYLD was lowly expressed in LC samples, and its knockdown elevated LC cell proliferation [13]. Moreover, low CYLD expression was confirmed to be associated with LC patient's poor prognosis [14]. This study screened the key ubiquitin ligase (E3)/DUB in LC samples through GEO database and UbiBrowser2.0 software, and found that CYLD was a DUB with a high score. However, the molecular mechanisms by which CYLD regulates LC progression still need to be further elucidated.

Kruppel-like factor 4 (KLF4) is a member of the zinc finger transcription factor family that exhibits an environment-dependent role during cancer development [15,16]. Previous studies showed that KLF4 played an anti-tumor function in LC progression, in which KLF4 upregulation repressed LC cell proliferation and metastasis [17,18]. Through JASPAR software prediction, our study found that KLF4 had binding sites with CYLD promoter. However, whether KLF4 regulates LC progression by mediating the transcription of CYLD is unknown. TEK receptor tyrosine kinase (TEK, also known as TIE2) has attracted much attention due to its crucial role in angiogenesis process [19], in which TEK overexpression has been confirmed to inhibit the phenotypic characteristics of lung adenocarcinoma (LUAD) [20]. The stability of TEK is usually controlled by the ubiquitin-proteasome system [21]. Through database screening, our study identified TEK as one of the deubiquitination substrates of CYLD, but the interaction between CYLD and TEK in LC has not been elucidated.

Our study delineated a comprehensive KLF4/CYLD/TEK signaling pathway in LC by integrating various research methods at the molecular, cellular and in vivo level, so as to provide a new framework for understanding the tumor suppression mechanism of LC.