Cip2a induces arginine biosynthesis and promotes tumor progression in non-small cell lung cancer.

Cancerous inhibitor of protein phosphatase 2A (Cip2a) is an oncoprotein, playing important roles in tumor progression. However, the underlying mechanisms by which Cip2a promotes tumor aggressiveness in NSCLC remain to be further investigated. In this study, we found that Cip2a expression is elevated in NSCLC and correlates with poor prognosis. Knockdown of Cip2a significantly reduced the ability of cell proliferation, invasion, and metastasis of NSCLC both in vitro and in vivo. Furthermore, we found that Cip2a promotes tumor progression partly by inducing arginine biosynthesis, and knockdown of Cip2a exhibited a significantly increased sensitivity to arginine deprivation and mTOR inhibition. In addition, we found that p53 mutants in NSCLC cells increased Cip2a expression by inhibiting the activity of wild-type p53. Our findings provide new insights into the mechanisms of Cip2a in promoting tumor progression and suggest that Cip2a represents a potential therapeutic target for treating NSCLC.

METTL14-mediated Bim mRNA m6A modification augments osimertinib sensitivity in EGFR-mutant NSCLC cells.

Resistance to osimertinib represents a significant challenge for the successful treatment of non-small cell lung cancer (NSCLC) harboring activating mutations in epidermal growth factor receptor (EGFR). N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates osimertinib resistance of NSCLC remains unknown. In this study, we demonstrated that developing osimertinib-resistant phenotypes depends on m6A reduction resulting from downexpression of m6A methyltransferase METTL14 in EGFR-mutant NSCLCs. Both in vitro and in vivo assay showed that specific knockdown of METTL14 was sufficient to confer osimertinib resistance and elevated expression of METTL14 rescued the efficacy of osimertinib in the resistant NSCLC cells. Mechanistically, METTL14 promoted m6A methylation of pro-apoptotic Bim mRNA and increased Bim mRNA stability and expression, resulting in activating the Bim-dependent pro-apoptotic signaling and thereby promoting osimertinib-induced cell apoptosis. Analysis of clinical samples revealed that decreased expression of METTL14 was observed in osimertinib-resistant NSCLC tissues and significantly associated with a poor prognosis. In conclusion, our study reveals a novel regulatory mechanism by which METTL14-mediated m6A methylation of Bim mRNA inhibited osimertinib resistance of NSCLC cells. It offers more evidences for the involvement of m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs. Implications: This study offers more evidences for the involvement of METTL14-mediated m6A modification in regulation of osimertinib resistance, and provides potential therapeutic targets for novel approaches to overcome the tolerance of osimertinib and other EGFR-TKIs.

Circ-FOXO3 inhibits triple-negative breast cancer growth and metastasis via regulating WHSC1-H3K36me2-Zeb2 axis.

Circular RNAs (circRNAs), a subclass of non-coding RNAs characterized by covalently closed continuous loops, play a key role in tumorigenesis and aggressiveness. However, the potential molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remains largely unknown. Exploring their roles and mechanisms in TNBC progression may help identify new diagnostic markers and therapeutic targets. In this study, we found that circ-FOXO3 was dramatically downregulated in TNBC tissues and blood samples from patients with TNBC. Notably, low circ-FOXO3 expression in TNBC tissues and bloods was associated with lymph node metastasis and unfavorable outcomes in patients with TNBC. Overexpression of circ-FOXO3 significantly inhibited the growth, invasion, and metastasis of TNBC cells both in vitro and in vivo. Moreover, we demonstrated that circ-FOXO3 was predominantly expressed in the cytoplasm and directly interacted with Wolf-Hirschhorn syndrome candidate 1 (WHSC1), thereby inhibiting WHSC1 nuclear localization and activity, resulting in the inhibition of H3K36me2 modifications at the Zeb2 promoter, ultimately inhibiting Zeb2 expression and halting TNBC growth and metastasis. Taken together, these results reveal the tumor-suppressive functions of circ-FOXO3 in inhibiting WHSC1-mediated H3K36me2 modification of Zeb2, suggesting that circ-FOXO3 could serve as a potential novel predictive prognostic biomarker and therapeutic target for TNBC.

P21-activated kinase 2-mediated ß-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer.

Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used for treating patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, acquired resistance to osimertinib is inevitable in EGFR-mutant NSCLC. By employing a global mass spectrometry-based phosphoproteomics approach, we identified that the activated p21-activated kinase 2 (PAK2)/ß-catenin axis acts as a driver of osimertinib resistance. We found that PAK2 directly phosphorylates ß-catenin and increases the nuclear localization of ß-catenin, leading to the increased expression and transcriptional activity of ß-catenin, which in turn enhances cancer stem-like properties and osimertinib resistance. Moreover, we revealed that HER3 as an upstream regulator of PAK2, drives the activation of PAK2/ß-catenin pathways in osimertinib-resistant cells. The clinical relevance of these findings was further confirmed by examining tissue specimens from patients with EGFR-mutant NSCLC. The results demonstrated that the levels of HER3, phospho-PAK2 (p-PAK2) and ß-catenin in the tissues from patients with EGFR-mutant NSCLC, that had relapsed after treatment with osimertinib, were elevated compared to those of the corresponding untreated tissues. Additionally, the high levels of HER3, p-PAK2 and ß-catenin correlated with shorter progression-free survival (PFS) in patients with EGFR-TKI-treated NSCLC. We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of ß-catenin is important for osimertinib resistance and targeting the HER3/PAK2/ß-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.