Identification of a novel target of SETD1A histone methyltransferase and the clinical significance in pancreatic cancer

• Published in: Cancer science Vol. 114; no. 2; pp. 463 - 476
• Main Authors: Ishii, Takeshi, Akiyama, Yoshimitsu, Shimada, Shu, Kabashima, Ayano, Asano, Daisuke, Watanabe, Shuichi, Ishikawa, Yoshiya, Ueda, Hiroki, Akahoshi, Keiichi, Ogawa, Kosuke, Ono, Hiroaki, Kudo, Atsushi, Tanabe, Minoru, Tanaka, Shinji
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.02.2023; John Wiley and Sons Inc
• Subjects: Adenocarcinoma; Antibodies; Carcinoma, Pancreatic Ductal - pathology; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Cell Proliferation - genetics; Chemotherapy; Clinical Relevance; Clinical significance; DNA helicase; Enzymes; Gene expression; Gene Expression Regulation, Neoplastic; Histone methyltransferase; Histone Methyltransferases - genetics; Histone Methyltransferases - metabolism; histone modification; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humans; Lymphatic system; Medical prognosis; Metastasis; Mutation; Original; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Prognosis; prognostic factor; RUVBL1; SETD1A; Stains & staining; Stem cells; Tumor cell lines; Tumorigenicity; Japan; pancreatic cancer; histone modification; prognostic factor; RUVBL1; SETD1A
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.15615

Although histone H3K4 methyltransferase SETD1A is overexpressed in various cancer types, the molecular mechanism underlying its overexpression and its target genes in pancreatic ductal adenocarcinoma (PDAC) remain unclarified. We conducted immunohistochemical staining for SETD1A in 105 human PDAC specimens to assess the relationship between SETD1A overexpression and clinicopathological features. The function and target genes of SETD1A were investigated using human pancreatic cancer cell lines. SETD1A expression was upregulated in 51.4% of patients with PDAC and was an independent prognostic factor associated with shorter disease‐free survival after resection (p < 0.05). Knockdown and overexpression of SETD1A showed that SETD1A plays a crucial role in increasing the proliferation and motility of PDAC cells. SETD1A overexpression increased tumorigenicity. RNA sequencing of SETD1A‐knockdown cells revealed downregulation of RUVBL1, an oncogenic protein ATP‐dependent DNA helicase gene. ChIP analysis revealed that SETD1A binds to the RUVBL1 promoter region, resulting in increased H3K4me3 levels. Knockdown of RUVBL1 showed inhibition of cell proliferation, migration, and invasion of PDAC cells, which are similar biological effects to SETD1A knockdown. High expression of both SETD1A and RUVBL1 was an independent prognostic factor not only for disease‐free survival but also for overall survival (p < 0.05). In conclusion, we identified RUVBL1 as a novel downstream target gene of the SETD1A‐H3K4me3 pathway. Co‐expression of SETD1A and RUVBL1 is an important factor for predicting the prognosis of patients with PDAC. RUVBL1 is a direct downstream target gene of SETD1A. High expression of both SETD1A and RUVBL1 is an independent prognostic factor not only for disease‐free survival but also for overall survival.