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Twist1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of Twist1

ABSTRACT: Non-small cell lung carcinoma (NSCLC) is a major cause of cancer mortality. High expression of the epithelial-to-mesenchymal transition transcription factor (EMT-TF) Twist1 is strongly associated with metastatic cancers and with treatment resistance. Twist1 can also upregulate O-GlcNAcylation to suppress fail-safe programs such as KrasG12D oncogene-induced senescence (OIS) that accelerates NSCLC tumorigenesis. We wanted to decipher the critical domains and transcriptional targets required for Twist1 acceleration of lung tumorigenicity. We created a novel genetically-engineered mouse model for autochthonous lung cancer through lung epithelial expression of KrasG12D oncogene (CR) concomitantly with Twist1wt (CRT) or a Twist1F191G transactivation-null mutant (CRF191G). Compared to CR and CRF191G, CRT mice had shorter tumor-free survival and more aggressive tumors histologically. CRT lung tumors also showed higher proliferation and lower cell-cycle arrest suggesting that the Twist1 transactivation-domain is important for OIS suppression. Supporting these data, we observed in non-cancer human bronchial epithelial cells (HBECs) that the co-expression of human TWIST1wt enhanced tumorigenic/invasive programs and could suppress HRasG12V-induced senescence while co-expressing TWIST1F187G transactivation-null mutant could not. TWIST1wt co-expression with HRasG12V in HBECs differentially modulated MYC downstream transcriptional programs. Finally, OIS induction in HBEC-HRasG12V-TWIST1wt was rescued by O-GlcNAcylation inhibition or by treatment with a novel MYC inhibitor MYCi975. Altogether, these results indicate that the Twist1 transactivation domain is required for Twist1-dependent acceleration of lung tumorigenesis via MYC and nominate MYCi975 as a means to activate latent OIS programs. MYC targeting strategies could limit pro-tumorigenic programs and serve as a therapeutic for TWIST1-overexpressing NSCLCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270902 | GEO | 2024/12/01

REPOSITORIES: GEO

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Project description:We have developed cdk4/hTERT-immortalized normal human bronchial epithelial cells (HBECs) to study lung cancer pathogenesis. By studying the oncogenic effect of common lung cancer alterations (p53, KRAS, and c-MYC) we demonstrate the ability of this model to characterize the stepwise transformation of bronchial epithelial cells to full malignancy. Using HBECs derived from multiple individuals we found: 1) the combination of five genetic alterations (p53, KRASV12, c-MYC, CDK4 and hTERT) is sufficient for full tumorigenic conversion of HBECs; 2) high levels of KRASV12 are required for full malignant transformation of HBECs, however these levels also stimulate oncogene-induced senescence; 3) RAS-induced senescence is largely bypassed with loss of p53 function; 4) over-expression of c-MYC greatly enhances malignancy but only in the context of sh-p53+KRASV12; 5) HBECs from different individuals vary in their sensitivity to transformation by these oncogenic manipulations; 6) serum-induced epithelial-to-mesenchymal transition (EMT) increases in vivo tumorigenicity; 7) genetically-identical clones of transformed HBECs exhibit pronounced differences in tumor growth, histology, and differentiation as well as sensitivity to standard platinum-based chemotherapies; and 8) an mRNA signature derived from tumorigenic and non-tumorigenic clones is predictive of outcome in lung cancer patients. Collectively, we demonstrate this HBEC model system can be used to study the effect of oncogenic mutations on malignant progression, oncogene-induced senescence, and EMT along with clinically translatable applications such as development of prognostic signatures and drug response phenotypes. Human bronchial epithelial cells (HBECs) immortalized with cdk4 and hTERT were transformed with p53 knockdown, KrasV12 and cMYC over-expression and profiled on Illumina HumanHT-12 V4.0 expression beadchips. Transformed HBECs were grown in two different growth media: KSFM (defined, serum-free medium) or R10 (RPMI with 10% FBS) as indicated. Clones were isolated from HBECs with sh-p53 + KrasV12 and sh-p53 + KrasV12 + cMYC.

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Twist1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of Twist1

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