Effect of TNIK upregulation on JQ1-resistant human colorectal cancer HCT116 cells

• Published in: Biochemical and biophysical research communications Vol. 530; no. 1; pp. 230 - 234
• Main Authors: Takahashi, Chihiro, Kondo, Shingo, Sadaoka, Kensuke, Ishizuka, Shuhei, Noguchi, Kohji, Kato, Yu, Sugimoto, Yoshikazu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.09.2020
• Subjects: Antineoplastic Agents - pharmacology; Azepines - pharmacology; BET protein; Bromodomain; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cyclin D1; Cyclin E1; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic - drug effects; HCT116 Cells; HEK293 Cells; Humans; Protein-Serine-Threonine Kinases - genetics; TNIK; Triazoles - pharmacology; Up-Regulation - drug effects; Bromodomain; TNIK; BET protein; Cyclin D1; Cyclin E1; Colorectal cancer
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2020.06.136

JQ1 disrupts the binding of bromodomain and extra-terminal (BET) family of proteins to acetylated histones, modulates the expression of various genes, and inhibits the proliferation of cancer cells. We established two JQ1-resistant sublines from human colorectal cancer HCT116 cells. These resistant cells showed an 8- to 9-fold higher resistance to JQ1, and a 2- to 4-fold higher resistance to various anti-cancer agents, such as doxorubicin, etoposide, mitoxantrone, SN-38, cisplatin, and methotrexate than the parental HCT116 cells. The JQ1-resistant cells expressed higher levels of TRAF2 and NCK-interacting protein kinase (TNIK), cyclin D1 (CCND1), cyclin E1 (CCNE1), and their corresponding mRNAs than the parental cells. TNIK is a regulator of Wnt/β-catenin signaling and is known to transactivate CCND1. Transient transfection of HCT116 cells with a TNIK expression plasmid resulted in the upregulation of cyclin D1, cyclin E1, and their corresponding mRNAs, as well as an increase in CCNE1 promoter activity. Furthermore, luciferase assay revealed that the JQ1-resistant cells showed high CCNE1 promoter activity. These results suggest that TNIK also transactivates CCNE1. Three stable TNIK transfectant clones of HEK293 cells expressed 1.5- to 2-fold higher levels of TNIK, cyclin D1, and cyclin E1 than the parental cells. The 293/TNIK-6 cells, which expressed the highest level of TNIK among the transfectants, showed a 2.3-fold higher resistance to JQ1 than the parental cells. These results suggest the possible involvement of TNIK in cellular resistance to JQ1. •Cross-resistance of JQ1-resistant cells to DNA-damaging agents.•Upregulation of TNIK, cyclin D1, and cyclin E1 in JQ1-resistant cells.•Upregulation of cyclin D1 and cyclin E1 in TNIK-transfected cells.•Increased CCNE1 promoter activity in JQ1-resistant cells and TNIK-transfected cells.•JQ1 resistance of stable TNIK-transfected cells.