Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation

Abstract

Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.

Clinical efficacy and potential mechanism of ginseng polysaccharides in the treatment of non-small cell lung cancer based on meta-analysis associated with network pharmacology

“…CCND1 is a crucial regulatory factor in tumor cells, which is capable of promoting tumor cell proliferation and inducing cell cycle arrest at the S phase [ 65 ]. siRNAs targeting CCND1 inhibit cancer progression by inducing apoptosis and suppressing tumor cell stemness and epithelial-mesenchymal transition [ 66 ]. HSP90AA1 can regulate a variety of biological processes.…”

Diagnostic validity of p16, E-cadherin, cyclin D1, p53, and HPV E6/E7 mRNA in CIN 3-like squamous cell carcinoma of the cervix

“…Epithelial-mesenchymal transition (EMT) (6-8) plays a significant role in tumor invasion and metastasis, with associated features including the high expression of cyclin D1 and loss of expression of E-cadherin. Previous studies have suggested that decreased expression of Ecadherin promotes poor adhesion and contributes to invasiveness and a poor prognosis (9)(10)(11). Because of the growth pattern characterized by a cell mass with a clear boundary, it is expected that CIN 3-like SCC exhibits an invasion or migration pattern of collective cells.…”

Targeted splicing therapy: new strategies for colorectal cancer

“…In terms of therapeutic strategies, research has shown that correcting CCND1 splicing through antisense oligonucleotides (ASO) and small molecule modulators can be effective in cancer therapy ( 67 ). These findings suggest that developing splicing regulatory drugs targeting CCND1 splicing variants could be a promising new option for the treatment of CRC.…”