The molecular mechanism underlying KRAS regulation on STK31 expression in pancreatic ductal adenocarcinoma

• Published in: Cancer science Vol. 115; no. 10; pp. 3288 - 3304
• Main Authors: Liu, Yuting, Tang, Shing Chun, Li, Chi Han, To, Ka Fai, Li, Bo, Chan, Stephen Lam, Wong, Chi Hin, Chen, Yangchao
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.10.2024; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Cell cycle; Cell growth; Cloning; Extracellular signal-regulated kinase; K-Ras protein; kinase; Kinases; KRAS; Laboratory animals; MAP kinase; Medical prognosis; Molecular modelling; Mutants; Mutation; Original; Pancreas; Pancreatic cancer; Plasmids; Point mutation; Protein-serine/threonine kinase; Signal transduction; siRNA; Software; Statistical analysis; STK31; Survival analysis; therapeutic target; Therapeutic targets; Transcription factors; Tumor cell lines; Tumors; STK31; kinase; pancreatic cancer; KRAS; therapeutic target
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16286

KRAS gene mutations are common in pancreatic ductal adenocarcinoma (PDAC), but targeting mutant KRAS is still challenging. Here, an endoribonuclease‐prepared small interfering RNA (esiRNA) library was used to screen new kinases that play critical roles in PDAC driven by KRAS gene mutations, and serine/threonine kinase 31 (STK31) was identified and characterized as a potential therapeutic target for KRAS‐mutant PDAC. Our results showed that STK31 was upregulated in KRAS‐mutant PDAC patients with poor survival and highly expressed in PDAC cell lines with KRASG12D mutation. Inhibition of STK31 in KRAS‐mutant cell lines significantly reduced PDAC cell growth in vitro and hindered tumor growth in vivo. Gain and loss of function experiments revealed that STK31 is a downstream target of KRAS in PDAC. A pharmacological inhibition assay showed MAPK/ERK signaling involved in STK31 regulation. The further mechanistic study validated that c‐Jun, regulated by KRAS/MAPK signaling, directly modulates the transcription level of STK31 by binding to its promoter region. Through RNA sequencing, we found that the cell cycle regulators CCNB1 and CDC25C are downstream targets of STK31. Taken together, our results indicate that STK31, which is the downstream target of the KRAS/MAPK/ERK/c‐Jun signaling pathway in KRAS‐mutant PDAC, promotes PDAC cell growth by modulating the expression of the cell cycle regulators CCNB1 and CDC25C. The novelty of our data lies in the identification and exploration of the molecular function and mechanism of STK31, a kinase identified through the screening of a kinase‐esiRNA library in KRAS‐mutant pancreatic ductal adenocarcinoma (PDAC). This study provides valuable insights into the role of STK31 in PDAC cell growth and its potential as a therapeutic target. Our findings contribute to the field by expanding the understanding of kinase‐mediated signaling in KRAS‐mutant PDAC and offering new possibilities for targeted PDAC treatment.