MYC/MAX-Activated LINC00958 Promotes Lung Adenocarcinoma by Oncogenic Transcriptional Reprogramming Through HOXA1 Activation

Abstract

BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The role of the long non-coding RNA (lncRNA) LINC00958, which regulates the malignant behavior of multiple tumors, in LUAD has not been elucidated.MethodsTissue microarray, FISH, and qRT-PCR were used to detect the expression of LINC00958. Plasmid and viral infections were used to manipulate gene expression. The role of LINC00958 in LUAD was studied by cell proliferation analysis, cell apoptosis analysis, cell migration and invasion analysis, and subcutaneous inoculation of animal models. At the same time, RNA-Seq, RNA pull-down, ChIRP, ChIP, and luciferase reporter gene assays were performed to clarify the mechanism.ResultsThe expression of LINC00958 in LUAD tissues was significantly upregulated when compared with that in adjacent tissues and could independently predict poor survival of patients with LUAD. LINC00958 knockdown significantly inhibited the growth and metastasis of lung cancer cells in vitro and in vivo. LINC00958 localized to the nucleus, regulated oncogenes and metabolism-related and immune response-related genes, and interacted with histones. The targets of LINC00958 were TRPV3, STAP2, and EDN2 promoters with motifs of HOXA1, NANOG, FOSL2, JUN, and ATF4. Moreover, HOXA1 overexpression mitigated the LINC00958 knockdown-induced oncogenic phenotype. MYC/MAX motif, which was detected at the cis-element of LINC00958, trans-activated the LINC00958 promoter.ConclusionsMYC/MAX-trans-activated LINC00958 promotes the malignant behavior of LUAD by recruiting HOXA1 and inducing oncogenic reprogramming.

Homeobox A1 Facilitates Immune Escape and Alleviates Oxidative Stress in Lung Adenocarcinoma

“…Particularly, our data confirmed the prominent upregulation of HOXA1 expression in LUAD than normal tissues, consistent with previous evidence [40]. HOXA1, a highly conserved homolog in humans, exerts critical roles in cell development and organ formation [41][42][43].…”

Potential Mechanisms of Metformin-Induced Apoptosis in HeLa Cells

“…Metformin affected the expression of PPP2R5C [ 32 ], PPP2R5A [ 33 ], and RRAGA genes in HeLa cells, and found that these genes were associated with signaling pathways such as AMPK, mTOR, and PI3K/AKT (Table S5) (Supplementary Materials) . In addition, some tumor-related genes, such as BEX2 , EDN2 , ANGPTL4 , and TP73 genes [ 34 , 35 ], were also involved in tumor suppression and transcription, tumorigenesis, tumor cell invasion, and encoding p53 family members. The CTH [ 36 ] gene encodes an enzyme that converts cystathionine from methionine to cysteine, while the CASP protein family is aspartate proteolytic enzymes containing cysteine, an enzyme that may be involved in the synthesis of CASP protein, thereby regulating apoptosis.…”

Integrated analysis of bulk and single-cell RNA-seq reveals the role of MYC signaling in lung adenocarcinoma

“…In contrast, MYC, as a transcription factor, can regulate the activation and expression of ncRNA, for example, the miR-15 and let-7 ( Adams and Eischen, 2016 ). In the study from Hou et al( Zhang et al, 2022 ), they found that the MYC/MAX-trans-activated LINC00958 could promote the malignant behavior of LUAD by recruiting HOXA1 and inducing oncogenic reprogramming.To further clarify the pathways in which MYC is involved, we calculated the enrichment scores of the 50 Hallmark pathways in MsigDB by the ssGSEA algorithm, and found differences in multiple Hallmark pathway enrichment scores between the two groups, a finding that was also consistent with previous studies. c-Myc, an important member of the MYC gene family, acts as a proto-oncogene localized to chromosome 8q24.1 and can be activated by chromosomal amplification, translocation, and rearrangement ( Xu-Monette et al, 2016 ).…”