The Role of Transcriptional Factor Brachyury on Cell Cycle Regulation in Non-small Cell Lung Cancer

Abstract

Lung cancer is the leading cause of cancer-related death, and non-small cell lung cancer (NSCLC) accounts for almost 80-85% of all lung cancer cases. The transcriptional factor brachyury has been verified to promote tumor cells migrate, invade, and metastasis in various types of tumors, whereas divergent roles of brachyury on cell proliferation have been reported in several types of tumor cells. In this study, we attempted to explore the effect of brachyury on the cell cycle progression and proliferation capability of NSCLC cells. Firstly, we performed RNA-sequence and ChIP-sequence to explore underlying downstream pathways regulated by brachyury. Cell proliferation and colony formation assays were utilized to detect the effect of brachyury on the proliferation ability of two types of lung NSCLC cells: H460 and Calu-1, which represent different brachyury expression levels. Following cell cycle and cell apoptosis assays were used to investigate the mechanism by which brachyury promotes NSCLC grow and progression. RNAsequence and ChIP-sequence (ChIP-seq) showed that one of the vital downstream pathways regulated by brachyury involves in cell cycle progression. Through cell proliferation assays and colony formation assays, we found that inhibition of brachyury could decrease the capability of proliferation in H460 cells. We also found that brachyury overexpression could prevent the transition from G0/G1 to S phase in Calu-1 cells, and brachyury knockdown could decrease the transition of G2/M phase in H460 cells. The cell apoptosis assays showed that inhibition of brachyury could promote apoptosis in H460 cells. In this study we demonstrate that brachyury and downstream target genes together involve in tumor cell cycle regulation by inducing accelerated transition through G2/M, promote tumor cell proliferation and inhibit apoptosis in lung NSCLC H460 cells. Targeting brachyury expression could be developed into a promising avenue for the prevention of lung cancer progression.

Knockdown of Brachyury Suppresses Breast Cancer Cell Proliferation and Migration via Targeting E2F3

“…The T-box protein Brachyury is a transcription factor that is widely expressed in multiple solid tumors and is associated with tumor aggressiveness and poor patient prognosis [ 25 ]. Our previous study has demonstrated that Brachyury and downstream target genes together involve in lung cancer cell cycle regulation by inducing accelerated transition through G2/M, promoting tumor cell proliferation and inhibiting apoptosis [ 15 ]. In addition, Brachyury has been proven to play an important role in promoting breast cancer cell progression [ 8 , 11 ].…”

“…Interestingly, previous studies have reported that Brachyury is expressed in mesodermal precursor cells, gradually downregulated during latestage embryos and is eventually undetectable in the majority of normal adulthood tissues [12]. More recently, Brachyury was described to be aberrantly overexpressed in several tumors, including lung [13][14][15], breast [11], prostate [16], colon [17], and testicular [18] cancer.…”

It’s high-time to re-evaluate the value of induced-chemotherapy for reinforcing immunotherapy in colorectal cancer

“…However, the SOC + immunotherapy regimen yielded biological activity in the form of substantial increases in multifunctional CD4+ and CD8+ T cells specific for the cascade antigens MUC1 and brachyury. Among them, the MUC1 and Brachyury pathways play important roles in cancer development and immune evasion and have become potential targets for tumor immunotherapy ( 202 , 203 ).…”

The role of transcriptional factor brachyury in the development and repair of nucleus pulposus

“…Transcription factor Brachyury, a protein of 435 amino acids, binds with the canonical T-domain DNA sequence: TCACACCT. Brachyury regulates posterior mesoderm formation and notochord differentiation by directly activating downstream mesoderm-specific genes (Chen et al, 2020a;Chen et al, 2020b;Xu et al, 2020). The embryonic notochord is considered to be the developmental origin of mature adult NP tissue (Richardson et al, 2017).…”