DPEP1 promotes drug resistance in colon cancer cells by forming a positive feedback loop with ASCL2

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 1; pp. 412 - 424
• Main Authors: Zeng, Cheng, Qi, Guoping, Shen, Ying, Li, Wenjing, Zhu, Qi, Yang, Chunxia, Deng, Jianzhong, Lu, Wenbin, Liu, Qian, Jin, Jianhua
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.01.2023; John Wiley and Sons Inc; Wiley
• Subjects: Antibodies; ASCL2; Basic Helix-Loop-Helix Transcription Factors - genetics; Bioinformatics; CD44 antigen; Cell growth; Chemotherapy; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colorectal cancer; Correlation analysis; Dipeptidase; DPEP1; Drug Resistance; Feedback; Genes; Genomes; Genotypes; Humans; Immunohistochemistry; Immunoprecipitation; Inflammatory bowel disease; Medical prognosis; Metastasis; Neoplastic Stem Cells - metabolism; Plasmids; Proteins; Software; Stem cells; Survival analysis; Transcription factors; Tumor cells; Ubiquitination; DPEP1; drug resistance; ASCL2; colon cancer; bioinformatics
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.4926

Background Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cell drug resistance remains unclear. Methods Dipeptidase 1 (DPEP1) expression was analyzed using the cancer genome atlas (TCGA) and genotype‐Tissue Expression pan‐cancer data. Survival analysis was performed using the survival package in R software to assess the prognostic value of DPEP1 expression in colon cancer. Correlation and Venn analyses were adopted to identify key genes. Immunohistochemistry, western blot, qRT–PCR, Co‐immunoprecipitation, and dual‐luciferase reporter experiments were carried out to explore the underlying associations between DPEP1 and Achaete scute‐like 2 (ASCL2). MTT assays were used to evaluate the role of DPEP1 and ASCL2 in colon cancer drug resistance. Results DPEP1 was highly expressed in colon cancer tissues. DPEP1 expression correlated negatively with disease‐specific survival but not with overall survival. Bioinformatics analysis and experiments showed that the expressions of DPEP1 and ASCL2 in colon cancer tissues were markedly positively correlated. Mechanistic research indicated that DPEP1 enhanced the stability of protein ASCL2 by inhibiting its ubiquitination‐mediated degradation. In turn, ASCL2 functioned as a transcription factor to activate the transcriptional activity of the DPEP1 gene and boost its expression. Furthermore, DPEP1 also could enhance the expression of colon cancer stem cell markers (LGR5, CD133, and CD44), which strengthened the tolerance of colon cancer cells to chemotherapy drugs. Conclusions Our findings reveal that the DPEP1 enhances the stemness of tumor cells by forming a positive feedback loop with ASCL2 to improve resistance to chemotherapy drugs. DPEP1 and ASCL2 formed a positive feedback loop regulation mode, which increased the tolerance of tumor cells to chemotherapeutic drugs. Thus, this study will provide a potentially important colon tumor drug resistance marker for clinical practice, and this positive feedback loop regulation will also provide a new perspective for tumor research.