PMID- 33477943 OWN - NLM STAT- MEDLINE DCOM- 20210730 LR - 20210730 IS - 2073-4425 (Electronic) IS - 2073-4425 (Linking) VI - 12 IP - 1 DP - 2021 Jan 19 TI - HEDGEHOG/GLI Modulates the PRR11-SKA2 Bidirectional Transcription Unit in Lung Squamous Cell Carcinomas. LID - 10.3390/genes12010120 [doi] LID - 120 AB - We previously demonstrated that proline-rich protein 11 (PRR11) and spindle and kinetochore associated 2 (SKA2) constituted a head-to-head gene pair driven by a prototypical bidirectional promoter. This gene pair synergistically promoted the development of non-small cell lung cancer. However, the signaling pathways leading to the ectopic expression of this gene pair remains obscure. In the present study, we first analyzed the lung squamous cell carcinoma (LSCC) relevant RNA sequencing data from The Cancer Genome Atlas (TCGA) database using the correlation analysis of gene expression and gene set enrichment analysis (GSEA), which revealed that the PRR11-SKA2 correlated gene list highly resembled the Hedgehog (Hh) pathway activation-related gene set. Subsequently, GLI1/2 inhibitor GANT-61 or GLI1/2-siRNA inhibited the Hh pathway of LSCC cells, concomitantly decreasing the expression levels of PRR11 and SKA2. Furthermore, the mRNA expression profile of LSCC cells treated with GANT-61 was detected using RNA sequencing, displaying 397 differentially expressed genes (203 upregulated genes and 194 downregulated genes). Out of them, one gene set, including BIRC5, NCAPG, CCNB2, and BUB1, was involved in cell division and interacted with both PRR11 and SKA2. These genes were verified as the downregulated genes via RT-PCR and their high expression significantly correlated with the shorter overall survival of LSCC patients. Taken together, our results indicate that GLI1/2 mediates the expression of the PRR11-SKA2-centric gene set that serves as an unfavorable prognostic indicator for LSCC patients, potentializing new combinatorial diagnostic and therapeutic strategies in LSCC. FAU - Sun, Yiyun AU - Sun Y AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Xu, Dandan AU - Xu D AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Zhang, Chundong AU - Zhang C AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Wang, Yitao AU - Wang Y AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Zhang, Lian AU - Zhang L AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Qiao, Deqian AU - Qiao D AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Bu, Youquan AU - Bu Y AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. FAU - Zhang, Ying AU - Zhang Y AUID- ORCID: 0000-0002-5414-6617 AD - Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China. AD - Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210119 PL - Switzerland TA - Genes (Basel) JT - Genes JID - 101551097 RN - 0 (Chromosomal Proteins, Non-Histone) RN - 0 (GANT 61) RN - 0 (GLI1 protein, human) RN - 0 (GLI2 protein, human) RN - 0 (Hedgehog Proteins) RN - 0 (Nuclear Proteins) RN - 0 (PRR11 protein, human) RN - 0 (Proteins) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 0 (RNA, Small Interfering) RN - 0 (SKA2 protein, human) RN - 0 (Zinc Finger Protein GLI1) RN - 0 (Zinc Finger Protein Gli2) SB - IM MH - Carcinoma, Non-Small-Cell Lung/*genetics/mortality/pathology MH - Cell Line, Tumor MH - Chromosomal Proteins, Non-Histone/*genetics MH - Datasets as Topic MH - Gene Expression Regulation, Neoplastic/drug effects/*genetics MH - Gene Knockdown Techniques MH - Hedgehog Proteins/metabolism MH - Humans MH - Kaplan-Meier Estimate MH - Lung/pathology MH - Lung Neoplasms/*genetics/mortality/pathology MH - Nuclear Proteins/antagonists & inhibitors/genetics/metabolism MH - Prognosis MH - Proteins/*genetics MH - Pyridines/pharmacology MH - Pyrimidines/pharmacology MH - RNA, Small Interfering/metabolism MH - RNA-Seq MH - Signal Transduction/drug effects/genetics MH - Transcriptional Activation/drug effects MH - Zinc Finger Protein GLI1/antagonists & inhibitors/genetics/metabolism MH - Zinc Finger Protein Gli2/antagonists & inhibitors/genetics/metabolism PMC - PMC7833434 OTO - NOTNLM OT - GLI OT - PRR11 OT - SKA2 OT - hedgehog OT - lung squamous cell carcinoma COIS- The authors declare no conflict of interest. EDAT- 2021/01/23 06:00 MHDA- 2021/07/31 06:00 PMCR- 2021/01/19 CRDT- 2021/01/22 01:03 PHST- 2020/11/11 00:00 [received] PHST- 2021/01/15 00:00 [revised] PHST- 2021/01/16 00:00 [accepted] PHST- 2021/01/22 01:03 [entrez] PHST- 2021/01/23 06:00 [pubmed] PHST- 2021/07/31 06:00 [medline] PHST- 2021/01/19 00:00 [pmc-release] AID - genes12010120 [pii] AID - genes-12-00120 [pii] AID - 10.3390/genes12010120 [doi] PST - epublish SO - Genes (Basel). 2021 Jan 19;12(1):120. doi: 10.3390/genes12010120.