Dataset Information

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

ABSTRACT: Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly understood. Here, using a cross-omics approach, YY2 is identified as a mitotic regulator that promotes SAC activity by activating the transcription of budding uninhibited by benzimidazole 3 (BUB3), a component of SAC. While both conditions induce CIN, a defect in YY2/SAC activity enhances mitosis and tumor growth. Meanwhile, hyperactivation of SAC mediated by YY2/BUB3 triggers a delay in mitosis and suppresses growth. Furthermore, it is revealed that YY2/BUB3-mediated excessive CIN causes higher cell death rates and drug sensitivity, whereas residual tumor cells that survived DNA damage-based therapy have moderate CIN and increased drug resistance. These results provide insights into the role of SAC activity and CIN levels in influencing tumor cell survival and drug response, as well as suggest a novel anti-tumor therapeutic strategy that combines SAC activity modulators and DNA-damage agents.

SUBMITTER: Hosea R

PROVIDER: S-EPMC11234461 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

Hosea Rendy R Duan Wei W Meliala Ian Timothy Sembiring ITS Li Wenfang W Wei Mankun M Hillary Sharon S Zhao Hezhao H Miyagishi Makoto M Wu Shourong S Kasim Vivi V

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240429 26

Spindle assembly checkpoint (SAC) is a crucial safeguard mechanism of mitosis fidelity that ensures equal division of duplicated chromosomes to the two progeny cells. Impaired SAC can lead to chromosomal instability (CIN), a well-recognized hallmark of cancer that facilitates tumor progression; paradoxically, high CIN levels are associated with better therapeutic response and prognosis. However, the mechanism by which CIN determines tumor cell survival and therapeutic response remains poorly und ...[more]

PMID: 38682484

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Project description:The liver is the most common site of metastasis for colorectal cancer (CRC). Metastasis suppressor 1 (MTSS1), a potential tumor suppressor gene associated with tumor metastasis, has been reported to play an important role in cancer development. The present study aimed to investigate the effects and underlying mechanisms of MTSS1 on the biological behavior of CRC cells both in vitro and in vivo. A CRC mouse model with a high liver metastatic potential was established by injecting mice with SW1116 cells, and the association between MTSS1 expression levels and the metastatic potential of forming liver metastasis lesions was subsequently analyzed. MTSS1 gain‑ and loss‑of‑function experiments were performed by transfecting the CRC cell lines, SW1116 and DLD‑1, with Plvx‑IRES‑ZsGreen1‑MTSS1 plasmid and short hairpin RNA, respectively. Cell proliferation, migration, invasion and cell cycle distribution were analyzed by MTT, Transwell and flow cytometric assays, respectively. To further determine the underlying mechanisms of MTSS1 in CRC, the expression levels of cell surface chemokine C‑X‑C receptor 4 (CXCR4) and its downstream signaling factors, Rac and cell division cycle 42 (CDC42), were analyzed with or without C‑X‑C motif chemokine ligand 12 (CXCL12) stimulation. The results revealed that as the CRC metastatic potential increased, the expression levels of MTSS1 decreased. The overexpression of MTSS1 exerted an inhibitory effect on cell proliferation, migration and invasion, while the knockdown of MTSS1 exerted the opposite effects in vitro. Flow cytometric analysis and western blot analysis demonstrated that MTSS1 negatively regulated the expression levels of cell surface CXCR4 and its downstream signaling pathway activation. On the whole, the results of the present study indicate that MTSS1 may play an important negative role in CRC metastasis and the underlying mechanisms may involve the downregulation of the CXCR4/CXCL12 signaling axis.

Project description:BackgroundIt remains presently unclear whether disease progression in colorectal carcinoma (CRC), from early, to invasive and metastatic forms, is associated to a gradual increase in genetic instability and to a scheme of sequentially occurring Copy Number Alterations (CNAs).MethodsIn this work we set to determine the existence of such links between CRC progression and genetic instability and searched for associations with patient outcome. To this aim we analyzed a set of 162 Chromosomal Instable (CIN) CRCs comprising 131 primary carcinomas evenly distributed through stage 1 to 4, 31 metastases and 14 adenomas by array-CGH. CNA profiles were established according to disease stage and compared. We, also, asked whether the level of genomic instability was correlated to disease outcome in stage 2 and 3 CRCs. Two metrics of chromosomal instability were used; (i) Global Genomic Index (GGI), corresponding to the fraction of the genome involved in CNA, (ii) number of breakpoints (nbBP).ResultsStage 1, 2, 3 and 4 tumors did not differ significantly at the level of their CNA profiles precluding the conventional definition of a progression scheme based on increasing levels of genetic instability. Combining GGI and nbBP,we classified genomic profiles into 5 groups presenting distinct patterns of chromosomal instability and defined two risk classes of tumors, showing strong differences in outcome and hazard risk (RFS: p?=?0.012, HR?=?3; OS: p?<?0.001, HR?=?9.7). While tumors of the high risk group were characterized by frequent fractional CNAs, low risk tumors presented predominantly whole chromosomal arm CNAs. Searching for CNAs correlating with negative outcome we found that losses at 16p13.3 and 19q13.3 observed in 10% (7/72) of stage 2-3 tumors showed strong association with early relapse (p?<?0.001) and death (p?<?0.007, p?<?0.016). Both events showed frequent co-occurrence (p?<?1x10-8) and could, therefore, mark for stage 2-3 CRC susceptible to negative outcome.ConclusionsOur data show that CRC disease progression from stage 1 to stage 4 is not paralleled by increased levels of genetic instability. However, they suggest that stage 2-3 CRC with elevated genetic instability and particularly profiles with fractional CNA represent a subset of aggressive tumors.

Dataset Information

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

Publications

YY2/BUB3 Axis promotes SAC Hyperactivation and Inhibits Colorectal Cancer Progression via Regulating Chromosomal Instability.

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