POU2F2 aggravates cell proliferation and autophagy in lung adenocarcinoma

Lung adenocarcinoma (LUAD) is one deadly tumor with high incidence. POU class 2 homeobox 2 (POU2F2) has been notarized to exhibit roles in the regulation of various cancers by playing as a facilitator. Our previous study demonstrated that POU2F2 is highly expressed and accelerates cell proliferation and motility in lung cancer. However, the additional regulatory functions of POU2F2 in LUAD progression require further investigations. In this study, we first confirmed through the UALCAN (A Portal for Facilitating Tumor Subgroup Gene Expression and Survival Analyses) online database that POU2F2 expression is elevated in LUAD tissues. Furthermore, we found that POU2F2 expression is up-regulated in LUAD cell lines. Functional experiments revealed that POU2F2 accelerates LUAD cell proliferation and enhances autophagy through increasing the LC3-II/LC3-I level and fluorescence intensity. Additionally, we discovered that POU2F2 activates the phosphoinositide dependent protein kinase 1 (PDPK1)-mediated phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) pathway. In conclusion, our discovery firstly disclose that POU2F2 exacerbates cell proliferation and autophagy in LUAD by modulating the PI3K/AKT pathway. This work suggests that POU2F2 may be a hopeful bio-marker for treating LUAD.

POU2F2; Lung adenocarcinoma; Autophagy; PI3K/AKT pathway

[1] Oberndorfer F, Müllauer L. Molecular pathology of lung cancer: current status and perspectives. Current Opinion in Oncology. 2018; 30: 69–76.

[2] Barta JA, Powell CA, Wisnivesky JP. Global epidemiology of lung cancer. Annals of Global Health. 2019; 85: 8.

[3] Yu JY, Chang H, Jung W, Heo S, Lee GT, Park JE, et al. Predicting mid-term survival of patients during emergency department triage for resuscitation decision. Signa Vitae. 2023; 19: 28–38.

[4] Wang L, Zhou L, Zhang J. Primary lung adenocarcinoma complicated with lung hamartoma: a case report and literature review. Journal of Central South University. 2022; 47: 529–534.

[5] Corcoran LM, Karvelas M, Nossal GJ, Ye ZS, Jacks T, Baltimore D. Oct-2, although not required for early B-cell development, is critical for later B-cell maturation and for postnatal survival. Genes & Development. 1993; 7: 570–582.

[6] Radomska HS, Shen CP, Kadesch T, Eckhardt LA. Constitutively expressed Oct-2 prevents immunoglobulin gene silencing in myeloma ´ T cell hybrids. Immunity. 1994; 1: 623–634.

[7] Ahmad I, Hoessli DC, Walker-Nasir E, Rafik SM, Shakoori AR, Nasir ud D. Oct-2 DNA binding transcription factor: functional consequences of phosphorylation and glycosylation. Nucleic Acids Research. 2006; 34: 175–184.

[8] Yang R, Wang M, Zhang G, Li Y, Wang L, Cui H. POU2F2 regulates glycolytic reprogramming and glioblastoma progression via PDPK1-dependent activation of PI3K/AKT/mTOR pathway. Cell Death & Disease. 2021; 12: 433.

[9] Wang SM, Tie J, Wang WL, Hu SJ, Yin JP, Yi XF, et al. POU2F2-oriented network promotes human gastric cancer metastasis. Gut. 2016; 65: 1427–1438.

[10] Ren W, Ren J, Zhang N, Liu X, Deng Y, Jiang Y, et al. CBX7 represses the POU2F2 to inhibit the PD-L1 expression and regulate the immune response in bladder cancer. Biochemical and Biophysical Research Communications. 2022; 613: 12–18.

[11] Li J, Li PT, Wu W, Ding BN, Wen YG, Cai HL, et al. POU2F2-mediated upregulation of lncRNA PTPRG-AS1 inhibits ferroptosis in breast cancer via miR-376c-3p/SLC7A11 axis. Epigenomics. 2024; 16: 215–231.

[12] Luo R, Zhuo Y, Du Q, Xiao R. POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1. BMC Pulmonary Medicine. 2021; 21: 117.

[13] Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell. 2011; 147: 728–741.

[14] Liu L, Ji X, Huang X. Dexmedetomidine improves myocardial ischemia-reperfusion injury by increasing autophagy via PINK1/PRKN pathway. Signa Vitae. 2022; 18: 125–132.

[15] Xu HM, Hu F. The role of autophagy and mitophagy in cancers. Archives of Physiology and Biochemistry. 2022; 128: 281–289.

[16] Russell RC, Guan KL. The multifaceted role of autophagy in cancer. The EMBO Journal. 2022; 41: e110031.

[17] Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nature Reviews Molecular Cell Biology. 2023; 24: 560–575.

[18] Yu Z, Tang H, Chen S, Xie Y, Shi L, Xia S, et al. Exosomal LOC85009 inhibits docetaxel resistance in lung adenocarcinoma through regulating ATG5-induced autophagy. Drug Resistance Updates. 2023; 67: 100915.

[19] Zhang J, Li MY, Lu X, Liu QX, Zhou D, Yang GX, et al. CWHM-1008 induces apoptosis and protective autophagy through the Akt/mTOR axis in LUAD cells. Journal of Oncology. 2021; 2021: 5548128.

[20] Wang Y, Li J, Zheng H, Wang K, Ren X, Wang G, et al. Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma. Cell Death Discovery. 2023; 9: 302.

[21] Zhu J, Ao H, Liu M, Cao K, Ma J. UBE2T promotes autophagy via the p53/AMPK/mTOR signaling pathway in lung adenocarcinoma. Journal of Translational Medicine. 2021; 19: 374.

[22] Yu B, Zhou Y, He J. TRIM13 inhibits cell proliferation and induces autophagy in lung adenocarcinoma by regulating KEAP1/NRF2 pathway. Cell Cycle. 2023; 22: 1496–1513.

[23] Liang J, Li H, Han J, Jiang J, Wang J, Li Y, et al. Mex3a interacts with LAMA2 to promote lung adenocarcinoma metastasis via PI3K/AKT pathway. Cell Death & Disease. 2020; 11: 614.

[24] Zheng Y, You H, Duan J, Chen B, Wu C, Chen P, et al. Centromere protein N promotes lung adenocarcinoma progression by activating PI3K/AKT signaling pathway. Genes & Genomics. 2022; 44: 1039–1049.

[25] Li M, Liu Z, Hou Z, Wang X, Shi H, Li Y, et al. Oncogenic zinc finger protein ZNF687 accelerates lung adenocarcinoma cell proliferation and tumor progression by activating the PI3K/AKT signaling pathway. Thoracic Cancer. 2023; 14: 1223–1238.

[26] Chen X, Zhu X, Shen X, Liu Y, Fu W, Wang B. IGF2BP3 aggravates lung adenocarcinoma progression by modulation of PI3K/AKT signaling pathway. Immunopharmacology and Immunotoxicology. 2023; 45: 370–377.