Abstract 5647: PTEN loss is associated with elevation of cell cycle signature in human glioblastoma transcriptome

Abstract

Abstract Glioblastoma is the most lethal type of brain cancer with universally poor prognosis. Despite advanced treatment, the cancer recurs frequently. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene whose mutations have been found to be one of the most frequent events in GBM. PTEN acts as a negative regulator of the phosphoinositide 3-kinase (PI3K) pathway. GBM transcriptome data from The Cancer Genome Atlas (TCGA) revealed a positive enrichment of cell cycle and PI3K pathway. Moreover, weighted gene co-expression network analysis (WGCNA) on TCGA GBMLGG cohort revealed a cell cycle-related module (‘cell-cycle’ module), which was shown to be positively correlated with PTEN mutation status. This ‘cell-cycle’ module also showed a positive correlation with glioma aggressiveness.We then utilized a nestin-cre;Pten-fl/fl mouse model to investigate the consequences of PTEN loss that may be involved in GBM. Based on our preliminary data, transcriptomic profiling of primary astrocytes derived from Pten knockout mice revealed an overlapping enrichment of cell cycle related pathways with human GBM. Four cell cycle genes, RCC1, RCC2, NEK2, and CHK2, were validated to be significantly upregulated in Pten-null astrocytes by qRT-PCR. Regulator of chromatin condensation 1 (RCC1) and Regulator of chromatin condensation 2 (RCC2) both belong to the RCC1 family. Accumulating evidence demonstrated that both RCC1 and RCC2 are involved in tumorigenesis of multiple cancers and cell cycle progression. By siRNA inhibition, we demonstrated that silencing of either RCC1 or RCC2 in glioblastoma cell lines suppresses GBM cell growth. Moreover, we found that RCC2 is essential for both G1-S and G2-M transition. Additionally, RCC2 silencing and a PI3K inhibitor LY294002 inhibit glioblastoma cell viability in a synergistic manner. In summary, PTEN deficiency leads to the alteration of cell cycle progression, which may promote tumorigenesis of glioblastoma. RCC1 and RCC2 have been demonstrated to be potential targets regulated by PTEN and affects cell viability. RCC2 was shown to be a key regulator of cell cycle progression. To further explore the RCC1 and RCC2 roles, we will find the potential downstream target of RCC1 and RCC2 and its potential therapeutic effect in vivo. Funding: This work is supported by a General Research Fund grant (#14113519) from the University Grants Committee of Hong Kong. Citation Format: Tian Liu, Penelope Mei-Yu Or, Chi-Wai Wong, Stanley Kwok-Kuen Cheung, Yubing Wang, Yiwei Wang, Wayne Lut-Heng Ho, Andrew M. Chan. PTEN loss is associated with elevation of cell cycle signature in human glioblastoma transcriptome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5647.