SIRT7 drives the radioresistance of pancreatic neuroendocrine tumours via the DNMT1-MEN1 axis

#4524

Introduction: Pancreatic neuroendocrine tumours (PanNETs) are a rare and highly heterogeneous type of tumour in the pancreas. After failure of standard treatment, patients have poor prognoses. Radiotherapy may be a potential therapeutic modality for such patients. However, PanNETs usually exhibit a radiation “cold” tumour through unclarified mechanisms.

Aim(s): To uncover the underlying molecular mechanism of radio resistance for preventing spontaneous tumour development in patients with high-risk PanNETs or preventing the recurrence of minimal residual tumour cells after a radical resection.

Materials and methods: In this study, SIRT7 is identified to be higher expressed in PanNETs and positively correlated with the staging of PanNETs. Upon exposure to ionising radiation (IR)-treatment condition, loss of SIRT7 compromised the survivability of PanNETs cells, as showed by decreased proliferation, colony formation, but increased apoptosis. Transcriptomic sequencing analysis indicated the apoptosis induced after SIRT7 knockdown was dependent on the upregulation of MEN1 expression. MEN1 is the most frequently mutated gene in PanNETs and encodes a typical tumour suppressor protein. Forced expression of SIRT7 largely inhibited MEN1 expression through the recruitment of DNMT1 to the promoter region of MEN1 whereas SIRT7 knockout promoted DNA damage and disrupted DNA damage repair (DDR) upon IR-treatment via MEN1 upregulation.

Conference:

Presenting Author: Jianyun J

Authors: Jiang J, Xu J, Liang Y, Chen L, Ji S,

Keywords: pancreatic neuroendocrine tumour, radio resistance, SIRT7, MEN1,