STK31 regulates the proliferation and cell cycle of lung cancer cells via the Wnt/β‑catenin pathway and feedback regulation by c‑myc

Abstract

Lung cancer, which is a leading cause of cancer-related deaths, is diagnosed at a male to female ratio of 2.1:1. Serine-threonine kinase 31 (STK31) is a novel cancer/testis (CT)-related gene that is highly expressed in several types of cancers, such as lung and colorectal cancer, and plays crucial roles in cancer. In the present study, increased expression of STK31 and β-catenin was observed in lung cancer tissues and cell lines. Downregulation of STK31 expression in lung cancer cells significantly inhibited their proliferation by arresting the cell cycle in the G1 phase concurrent with decreased β-catenin, c-myc and cyclin D1 protein levels, while upregulation of STK31 had the opposite effects. In addition, STK31-induced lung cancer cell viability, proliferation, cell cycle progression, and expression of related genes were completely attenuated by a Wnt/β-catenin inhibitor (XAV939). Similar to XAV939, a c-myc inhibitor (10058-F4) also significantly attenuated STK31-induced proliferation and cell cycle progression in lung cancer cells. Inhibiting c-myc and TRRAP significantly decreased the expression of STK31, and a chromatin immunoprecipitation (ChIP) assay confirmed that c-myc directly bound to the STK31 promoter. These results indicated that STK31 may act as an oncogene in lung cancer and that c-myc may be the transcription factor that promotes STK31 expression. Moreover, the results suggested that c-myc can also regulate STK31 expression in a positive feedback loop, and the downregulation of STK31 in lung cancer cells had an inhibitory effect on cell viability, cell proliferation and cell cycle progression, likely by inactivating the Wnt/β-catenin pathway and positive feedback regulation by c-myc.

Cancer‐testis gene STK31 is regulated by methylation and promotes the development of pancreatic cancer

“…STK31 was reported to promote cell proliferation in lung cancer cells by the Wnt/β‐catenin signaling pathway and positive feedback regulation of c‐myc. 13 In general, the oncogenic role of STK31 indicated by the present study was consistent with previous reports. However, some results in this study should be taken carefully.…”

“… 10 In addition, STK31 has also been detected in gastric cancer, 11 colorectal cancer, 12 cervical cancer, 12 and lung cancer. 13 The biological functions of STK31 such as maintaining the undifferentiated state, 14 promoting cell proliferation, and cell cycle regulation, has been studied in regards to these conditions. 15 It's been found in our previous studies that the high expression of STK31 suggested a poor prognosis of PC.…”

MicroRNA-543 controls pancreatic cancer development by LINC00847-microRNA-543-STK31 axis

“…Serine/threonine kinase 31 (STK31) controls tumorigenicity via control of differentiation states, suggesting that STK31 may be controlled by an epigenetic mechanism ( 9 ). Recent research reported that STK31 controlled the cell growth and cell cycle of lung cancer cells via the Wnt/beta-catenin pathway ( 10 ), maintained the undifferentiated state of colon cancer cells ( 9 ), and was a novel biomarker of colorectal cancer ( 11 ). Interestingly, there are few studies on the mechanism of STK31 in PC.…”

The Clinicopathologic and Prognostic Significance of c-Myc Expression in Hepatocellular Carcinoma: A Meta-Analysis

“…Cancer cell behaviors and activities, such as cell growth, survival, resistance to chemotherapies, immune surveillance, and metastasis, are also controlled by these effectors of c-Myc. c-Myc can regulate carcinogenesis and progression in many cancers, including lung cancer ( Xiong et al, 2020 ), breast cancer ( Chen et al, 2020 ), and colorectal cancer ( Pan et al, 2020 ). c-Myc also plays an important role in the occurrence and development of HCC ( Cheng et al, 2015 ; Attallah et al, 2017 ).…”