Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer

doi:10.1007/s11684-023-1053-3

2024, Vol. 18

Issue (4) : 721-734 https://doi.org/10.1007/s11684-023-1053-3

Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer

Yuanxin Yao¹, Honghui Lv^2,¹, Meiying Zhang¹, Yuan Li^3,¹, James G. Herman⁴, Malcolm V. Brock⁵, Aiai Gao¹, Qian Wang¹, Francois Fuks⁶, Lirong Zhang²(

), Mingzhou Guo^1,⁷(

)

¹. Department of Gastroenterology and Hepatology, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
². Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China
³. Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou 450001, China
⁴. UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
⁵. Department of surgery, School of Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
⁶. Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Center (U-CRC), Universite Libre de Bruxelles (ULB), Brussels 1070, Belgium
⁷. National Key Laboratory of Kidney Diseases, the First Medical Center, Chinese PLA General Hospital, Beijing 100853, China

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Abstract

Synthetic lethality is a novel model for cancer therapy. To understand the function and mechanism of BEN domain-containing protein 4 (BEND4) in pancreatic cancer, eight cell lines and a total of 492 cases of pancreatic neoplasia samples were included in this study. Methylation-specific polymerase chain reaction, CRISPR/Cas9, immunoprecipitation assay, comet assay, and xenograft mouse model were used. BEND4 is a new member of the BEN domain family. The expression of BEND4 is regulated by promoter region methylation. It is methylated in 58.1% (176/303) of pancreatic ductal adenocarcinoma (PDAC), 33.3% (14/42) of intraductal papillary mucinous neoplasm, 31.0% (13/42) of pancreatic neuroendocrine tumor, 14.3% (3/21) of mucinous cystic neoplasm, 4.3% (2/47) of solid pseudopapillary neoplasm, and 2.7% (1/37) of serous cystic neoplasm. BEND4 methylation is significantly associated with late-onset PDAC (> 50 years, P < 0.01) and tumor differentiation (P < 0.0001), and methylation of BEND4 is an independent poor prognostic marker (P < 0.01) in PDAC. Furthermore, BEND4 plays tumor-suppressive roles in vitro and in vivo. Mechanistically, BEND4 involves non-homologous end joining signaling by interacting with Ku80 and promotes DNA damage repair. Loss of BEND4 increased the sensitivity of PDAC cells to ATM inhibitor. Collectively, the present study revealed an uncharacterized tumor suppressor BEND4 and indicated that methylation of BEND4 may serve as a potential synthetic lethal marker for ATM inhibitor in PDAC treatment.

Keywords BEND4 DNA methylation synthetic lethality NHEJ pathway

Corresponding Author(s): Lirong Zhang,Mingzhou Guo

Just Accepted Date: 16 May 2024 Online First Date: 28 June 2024 Issue Date: 30 August 2024

Cite this article:

Yuanxin Yao,Honghui Lv,Meiying Zhang, et al. Epigenetic silencing of BEND4, a novel DNA damage repair gene, is a synthetic lethal marker for ATM inhibitor in pancreatic cancer[J]. Front. Med., 2024, 18(4): 721-734.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1053-3
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I4/721

Fig.1 Expression and methylation status of BEND4 in PDAC cells and tissue samples. (A) The association of BEND4 expression and CpG site methylation in the promoter region extracted from the TCGA database. (B) RT-PCR and (C) MSP results of BEND4 in PDAC cells. 5-aza: 5-aza-2′-deoxycytidine; GAPDH: internal control; U: unmethylation; M: methylation; IVD: in vitro methylated DNA, serves as methylation control; NL: normal peripheral lymphocytes DNA, serves as unmethylation control. (D) BSSQ results of BEND4 in PDAC cells. MSP product size is 143 bp, and BSSQ was amplified for 301 bp (from −324 to −23) encompassing the MSP product in the promoter region. Filled circles: methylated CpG sites; open circles: unmethylated CpG sites; TSS: transcription start site. (E) Representative MSP results of BEND4 in pancreatic neoplasms. PN: noncancerous pancreatic tissue samples; IPMN: intraductal papillary mucinous neoplasm; PDAC: pancreatic ductal adenocarcinoma. (F) Representative IHC staining of BEND4 in PDAC and adjacent noncancerous tissue samples. Scale bar: 50 μm (up); 20 μm (down). (G) IHC score of BEND4 in PDAC and adjacent noncancerous tissue samples. Data are presented as mean ± SD. (H) The association of BEND4 expression and promoter region methylation in PDAC. (I) Kaplan–Meier curve shows the association of BEND4 methylation and OS in patients with PDAC (n = 207). ****P < 0.0001.

Tab.1 Association of BEND4 methylation and clinical factors in PDAC

Tab.2 Univariate and multivariate analyses of BEND4 methylation status with the overall survival of patients with PDAC

Fig.2 Effect of BEND4 on PDAC cell proliferation, colony formation, cell cycle, apoptosis, migration, invasion, and tumor xenograft model. (A) Cell proliferation was evaluated by MTT assay. Vector: empty vector control; BEND4: BEND4 expressing vector. WT: wild-type control; KO: BEND4 knockout. (B) Representative colony formation results. (C) Flow cytometry shows cell cycle results. (D) Levels of checkpoint proteins in PDAC cells without or with BEND4 expression. β-actin: internal control. (E) BEND4 induces apoptosis in PDAC cells. Scr: scramble control. (F) Levels of key apoptotic proteins in PDAC cells without or with BEND4 expression. (G) BEND4 suppresses migration and invasion in PDAC cells. (H) Levels of metastatic proteins in PDAC cells without or with BEND4 expression. (I) Representative pictures of BEND4 unexpressed and re-expressed SW1990 cell xenografts. (J) Growth curves and (K) Tumor weight of BEND4 unexpressed and re-expressed SW1990 cell xenografts (n = 6). The results are presented as the mean ± SD of three replicates. *P < 0.05, ***P < 0.001, ****P < 0.0001.

Fig.3 BEND4 promotes DNA damage repair through NHEJ. (A) Co-IP assay and silver staining. Red arrow: differential band. (B) Co-IP (up) and reciprocal Co-IP (down) validation of BEND4 binding with Ku80. (C) Comet assay in PDAC cells before and after cisplatin treatment. (D) Levels of NHEJ proteins in PDAC cells before and after cisplatin treatment. The results are presented as the mean ± SD of three replicates. ns, no significance. ****P < 0.0001.

Fig.4 BEND4 involves the NHEJ signaling pathway by interacting with Ku80. (A) HR and NHEJ efficiency were evaluated in U2OS-DR-GFP and U2OS-EJ5 cells before and after BEND4 knockdown. (B) Co-IP assay to show the interaction of Ku70, Ku80, and DNAPKcs in BEND4 unexpressed and overexpressed SW1990 cells. (C) Ku70, Ku80, and DNAPKcs in whole-cell lysates and chromatin fraction of PDAC cells after cisplatin treatment. (D) Comet assay in PDAC cells before and after knockdown of Ku80. (E) Levels of NHEJ proteins before and after Ku80 knockdown. The results are presented as the mean ± SD of three replicates. ns, no significance. *P < 0.05, ****P < 0.0001.

Fig.5 Loss of BEND4 expression sensitized PDAC cells to AZD0156. (A) IC₅₀ assay to show the sensitivity of PDAC cells to AZD0156. (B) Representative colony formation results to show the synthetic lethality between AZD0156 and BEND4 defect. (C) Levels of ATM/CHK2 signaling and γ-H2AX in cells under different combination of treatment with cisplatin and AZD0156. The results are presented as the mean ± SD of three replicates. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

Fig.6 Synthetic lethality of BEND4 methylation and ATM inhibitor in vivo. (A) Tumor growth curves of BEND4 unexpressed and re-expressed SW1990 cell xenografts under different combinations of treatment with cisplatin and AZD0156. (B) Normalized tumor volume and (C) weight in BEND4 unexpressed and re-expressed SW1990 cell xenografts. (D) Representative IHC results to show the levels of NHEJ proteins in SW1990 cell xenografts under cisplatin treatment. (E) A working model for synthetic lethality of BEND4 methylation and ATM inhibitor in PDAC cells. M: DNA methylation; NHEJ: non-homologous end joining; HR: homologous recombination. ***P < 0.001, ****P < 0.0001.

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