DNMT3B and TET1 mediated DNA methylation of LATS1 regulates BC progression via hippo signaling pathway

Nowadays, BC is the malignant cancer with the highest incidence rate in the world, existing comprehensive treatments, including surgery, radiotherapy and systemic drugs can significantly improve the prognosis of patients. The 5-year survival rate of early BC is more than 90%, the 5-year survival rate of mid-stage BC is between 60% and 80% after surgery plus adjuvant chemotherapy and radiotherapy, and the 5-year survival rate of advanced BC is approximately 30% [1]. Epidemiological data of 320,179 cases of BC in Holland showed that the 10 year overall survival rates of I and II-III BC patients reached 94% and 75%, respectively [2]. However, the distant metastasis of IV BC is only 9% [2]. In addition, about 6% of BC patients were diagnosed with distant organ metastasis from bone, liver and lung at the initial diagnosis [3], [4], [5], [6], [7], [8], [9].

Hippo signaling pathway is an important signaling pathway in the body regulating cell proliferation and organ size [10], [11], [12], [13]. LATS1, as one of the core factors of Hippo signaling pathway, has plasticity in its expression state and shows obvious functional differences in different states [14]. The activation of LATS1 (phosphorylated) can limit the expression of downstream Yes-associated protein (YAP), inhibit the expression of tumor apoptosis suppressors such as KI67, SOX4, cIAP-1 and cell proliferation-related factors, and participate in the inhibition of tumor development. Inactivated LATS1 (nonphosphorylated) loses the function of phosphorylated YAP protein, resulting in a decrease of p-YAP [15]. Nonphosphorylated YAP enters the nucleus to function as a nuclear transcription factor, leading to EMT key proteins expression, damaging the polarity of normal cells [16], [17], [18], [19]. The expression and dysfunction of key proteins of Hippo signaling pathway (LATS1, YAP, MST1/2) significantly promote the malignant progression of tumor cells [20]. In the malignant progression of BC, LATS1, which should play a role in inhibiting tumor development, switches to an inactive state, which is the key to studying the malignant development of BC [21], [22]. In triple-negative breast cancer (TNBC), CD146 promotes radiation resistance in tumor cells in vitro and in vivo by activating YAP protein and driving its relocalization from plasma to nucleus by regulating LATS1, promoting repair of aberrant DNA damage, and inducing EMT and stem cells [23]. In addition, CD146 can form novel coreceptor complexes with integrin β1 and induce radiation resistance in breast cancer [23]. In breast cancer, overexpression of LIN28 significantly induced the expression of YAP and reduced the transcription of YAP upstream kinases (such as MST1/2 and LATS1/2) [24]. The research on the mechanism of action shows that LIN28 recruits the RNA binding protein MSI2 in a way that depends on the LIN28 CSD domain and the RRM domain of MSI2, rather than relying on Let-7, to directly induce the mRNA decay of YAP upstream kinase, leading to the inhibition of Hippo pathway and the activation of YAP, ultimately leading to the increase of tumor stem cell population, the promotion of tumor cell growth and the enhancement of invasive phenotype [24].

The abnormal transformation between activated and inactive forms, the imbalance of protein expression is critical for tumorigenesis [25]. Scientific evidence shows that inactivated LATS1 promotes YAP to play a transcriptional regulatory role, promotes the division and proliferation of tumor cells, destroys the histological barrier of tumor cell invasion, creates conditions for tumor invasion, and facilitates the separation and abscission of tumor cells from the primary focus and invasion and metastasis [26], [27]. Number of studies have found that epigenetic changes are the main causes of gene inactivation, DNA methylation is the key epigenetic event causing LATS1 inactivation [28], [29], [30], [31]. Clearly numerous CpG island sites can be methylated in the promoter region of LATS1 gene [32]. LATS1 is methylated and inactivated in a various tumors, activates YAP, regulates various cancer promoting factors, and promotes tumor metastasis and malignant development; its specific mechanism has not been fully clarified.

DNA methylation is under the action of DNA methyltransferases (DNMTs), the cytosine at the 5′- end of CpG dinucleotide is transformed into 5′-methylcytosine, thereby inhibiting the normal expression of genes [33]. DNA methylation modification is a reversible dynamic process; 5-methylcytosine (5mC) can be removed through DNA demethylation process to inhibit the DNA methylation level of genes and induce gene reactivation and expression [34], [35]. DNA demethylation can be completed through two processes: passive demethylation and active demethylation; active demethylation of DNA is the key of the whole process [36]. DNA active demethylation is periodic, starting from 5mC and ending with unmodified C [37], [38]. In summary, it has been widely reported by scholars that the methylation of LATS1 gene causes disorder of the Hippo signal pathway regulating cell proliferation and apoptosis and promoting the malignant development of tumors [39]. However, the mechanism of the regulation of DNA methylation of LATS1 gene is unclear. Whether active demethylation is the key to the change in DNA methylation modification of LATS1 gene of BC.

留言 (0)

沒有登入
gif