The role of USP24 in lung cancer proliferation malignancy and tumor-associated microenvironment

Abstract

Ubiquitin is a critical modifier that regulates the degradation and function of its target proteins via post-translational modification Numerous studies have found that E3 ligases which can join ubiquitin molecules and substrates with covalent bonds are related with cancer formation; however the relation between deubiquitinating enzymes and cancer is still unclear In this study we elucidated multiple roles of a novel deubiquitinating enzyme ubiquitin-specific peptidase 24 (USP24) in lung cancer progression First we found that activation of EGFR signaling pathway caused USP24 phosphorylation and downregulation resulting in the degradation of its substrates Bax and p300 and the decrease of Ku70 acetylation therefore attenuating cancer cell apoptosis Second we found other substrates of USP24 such as E2F4 and securin were also decreased after USP24 downregulation resulting in the acceleration of cancer cell proliferation through increasing G1/S transition and metaphase/anaphase transition Moreover the downregulated E2F4 led to the upregulation of RAD51 which is a crucial gene for DNA damage repair and led to CPT resistance Downregulated USP24-induced DNMT1 (DNA methyltransferases 1) upregulation might also involved in DNA damage repair through increasing RAD54L expression In the late stage of lung cancer we found that single nucleotide polymorphism (SNP) and RNA editing of USP24 increased USP24 level by increasing its RNA stability Upregulated USP24 could promote metastasis through stabilizing E3 ligase MDM2 resulting in the decrease of methyltransferase Suv39h1 and decrease of histone H3 lysine-9 methylation We also found that USP24 was upregulated when monocyte differentiates into tumor-associated M2 macrophages Increased USP24 might induce interleukin 6 (IL-6) expressions and secretion in tumor-associated microenvironment through regulating p300 and NF-?B expression or IL-6 promoter methylation and promote cancer metastasis Based on these results we have proved that USP24 plays important roles in cancer cell apoptosis proliferation drug resistance metastasis and tumor associated microenvironment By elucidating these detail mechanisms we hope we can provide new diagnostic and therapeutic strategies for lung cancer treatment

Date of Award	2017 May 18
Original language	English
Supervisor	Jan-Jong Hung (Supervisor)