Study on the regulation of cap-dependent protein translation of EZH2 by HOXC8 in Cr(VI)-exposed BEAS-2B Cells

LIU Mengdan; CHEN Jiahong; SUN Ruohan; ZHU Yongfei; ZHANG Yujing

PDF(6001 KB)

Journal of Hunan Normal University(Medical Science) ›› 2025, Vol. 22 ›› Issue (1) : 31-38.

Basic Medicine

Study on the regulation of cap-dependent protein translation of EZH2 by HOXC8 in Cr(VI)-exposed BEAS-2B Cells

LIU Mengdan¹, CHEN Jiahong¹, SUN Ruohan¹, ZHU Yongfei¹, ZHANG Yujing^1,2

Author information +

History +

Abstract

Objective To investigate the regulatory effect of homeobox gene C8 (HOXC8) on zeste enhancer homologue 2(EZH2) during the malignant transformation of BEAS-2B cells induced by long-term hexavalent chromium [Cr(VI)] exposure, this study may provide a clue to the molecular mechanism of Cr(VI)-induced chronic lung injury. Methods Cell counting, clone formation experiment, soft agar experiment and cell sphere formation experiment were used to detect the changes of cell proliferation and anchorage-independent growth ability. TIMER2.0, HPA and Kaplan-Meier databases were used to analyze the expression of HOXC8 in lung cancer and its influence on the survival rate of patients with lung cancer. BEAS-2B and A549 cell lines were constructed by lentivirus technology. The real-time quantitative PCR was used to detect the mRNA expression of HOXC8. The expression of HOXC8, EZH2 and related proteins of mammalian Sirolimus target proteins(mTOR) were analyzed by Western Blot. Dual-luciferase reporter assay detected altered EZH2 cap-dependent protein translation in HOXC8-overexpressed A549 cells and Cr(VI)-exposed BEAS-2B cells. Results Compared with the control group, the proliferative capacity of BEAS-2B cells exposed to Cr(VI) for a long time is significantly enhanced, and they show a relatively strong anchorage-independent growth ability. The results of bioinformatics analysis show that the expression of HOXC8 in lung cancer is significantly increased. Immunohistochemical results indicate that the expression of HOXC8 in lung cancer tissues is significantly increased, and HOXC8 is closely related to the recurrence-free survival rate of lung cancer patients. The expressions of HOXC8, EZH2 and protein translation-related mTOR signaling pathway proteins mTOR and 4EBP-1 are increased in Cr(VI)-exposed cells. Inhibiting the expression of HOXC8 can reduce the abnormal cell proliferation caused by Cr(VI) exposure and the expressions of EZH2, mTOR and 4EBP1, and can also inhibit the cap-dependent protein translation process of EZH2. In addition, inhibiting the expression of HOXC8 in A549 cells can also reduce the cap-dependent protein translation of EZH2. Conclusion HOXC8 regulates EZH2 cap - dependent protein translation via the mTOR signaling pathway in Cr(VI)-induced malignantly transformed BEAS - 2B cells.

Key words

hexavalent chromium / homeobox gene C8 / enhancer of zeste homolog 2 / cap-dependent protein translation

Cite this article

EndNote

Ris (Procite)

Bibtex

Download Citations

LIU Mengdan, CHEN Jiahong, SUN Ruohan, ZHU Yongfei, ZHANG Yujing. Study on the regulation of cap-dependent protein translation of EZH2 by HOXC8 in Cr(VI)-exposed BEAS-2B Cells[J]. Journal of Hunan Normal University(Medical Science). 2025, 22(1): 31-38

References

[1] SINGH V, SINGH N, VERMA M, et al.Hexavalent-Chromium-Induced Oxidative Stress and the Protective Role of Antioxidants against Cellular Toxicity[J]. Antioxidants (Basel, Switzerland), 2022, 11(12): 2375-2388.
[2] CHAKRABORTY R, RENU K, ELADL M A, et al.Mechanism of chromium-induced toxicity in lungs, liver, and kidney and their ameliorative agents[J]. Biomed Pharmacother, 2022, 151: 113119.
[3] XIE H, WISE S S, HOLMES A L, et al.Carcinogenic lead chromate induces DNA double-strand breaks in human lung cells[J]. Mutat Res, 2005, 586(2): 160-172.
[4] BEHRENS T, GE C, VERMEULEN R, et al.Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY)[J]. Int J Cancer, 2023, 152(4): 645-660.
[5] WANG Z, UDDIN MB, XIE J, et al.Chronic Hexavalent Chromium Exposure Upregulates the RNA Methyltransferase METTL3 Expression to Promote Cell Transformation, Cancer Stem Cell-Like Property, and Tumorigenesis[J]. Toxicol S, 2022, 187(1): 51-61.
[6] ENTEZARI M, TAHERIAZAM A, PASKEH M D A, et al. The pharmacological and biological importance of EZH2 signaling in lung cancer[J]. Biomed Pharmacother, 2023, 160: 114313.
[7] LIU H, ZHANG M, XU S, et al.HOXC8 promotes proliferation and migration through transcriptional up-regulation of TGFβ1 in non-small cell lung cancer[J]. Oncogenesis, 2018, 7(2): 1-15.
[8] ZHENG X, PANG Y, HASENBILIGE, et al. ATF4-mediated different mode of interaction between autophagy and mTOR determines cell fate dependent on the level of ER stress induced by Cr(VI)[J]. Ecotoxicol Environ Saf, 2024, 281: 116639.
[9] YANG R, WANG M, ZHANG G, et al.E2F7-EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression[J]. Br J Cancer, 2020, 123(9): 1445-1455.
[10] YATERA K, MORIMOTO Y, UENO S, et al.Cancer Risks of Hexavalent Chromium in the Respiratory Tract[J]. J UOEH, 2018, 40(2): 157-172.
[11] TSUNETA Y, OHSAKI Y, KIMURA K, et al.Chromium content of lungs of chromate workers with lung cancer[J]. Thorax, 1980, 35(4): 294-297.
[12] MAYBAUER M O, EL BANAYOSY A, KOERNER M M, et al.Mechanical cardiopulmonary resuscitation for venoarterial ECMO implantation in pulmonary embolism complicated by type B aortic dissection and retroperitoneal hemorrhage[J]. J Card Surg, 2020, 35(10): 2821-2824.
[13] ZHANG L, LI N, ZHANG X, et al.Hexavalent chromium caused DNA damage repair and apoptosis via the PI3K/AKT/FOXO1 pathway triggered by oxidative stress in the lung of rat[J]. Ecotoxicol Environ Saf, 2023, 267: 115622.
[14] CHEN W, CHEN Z, JIA Y, et al.Circ_0008657 regulates lung DNA damage induced by hexavalent chromium through the miR-203a-3p/ATM axis[J]. Environ Int, 2024, 185: 108515.
[15] NA F, PAN X, CHEN J, et al.KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming[J]. Nature Cancer, 2022, 3(6): 753-767.
[16] LI L, WANG Y, SONG G, et al.HOX cluster-embedded antisense long non-coding RNAs in lung cancer[J]. Cancer Letters, 2019, 450: 14-21.
[17] ZHANG J, YANG M, LI D, et al.Homeobox C8 is a transcriptional repressor of E-cadherin gene expression in non-small cell lung cancer[J]. Int J Biochem Cell Biol, 2019, 114: 105557.
[18] LLOVERA M, GARCÍA-MARTÍNEZ C, LÓPEZ-SORIANO J, et al. Role of TNF receptor 1 in protein turnover during cancer cachexia using gene knockout mice[J]. Mol Cell Endocrinol, 1998, 142(1-2): 183-189.
[19] ZHAO J, OHSUMI T K, KUNG J T, et al.Genome-wide identification of polycomb-associated RNAs by RIP-seq[J]. Mol Cell, 2010, 40(6): 939-953.
[20] HE Y, MENG X M, HUANG C, et al.Long noncoding RNAs: Novel insights into hepatocelluar carcinoma[J]. Cancer Letters, 2014, 344(1): 20-27.
[21] GUERRA S L, MAERTENS O, KUZMICKAS R, et al. A deregulated HOX gene axis confers an epigenetic vulnerability in KRAS-mutant lung cancers[J]. Cancer cell, 2020, 37(5): 705-719. e6.
[22] KAUR P, SHANKAR E, GUPTA S.EZH2-mediated development of therapeutic resistance in cancer[J]. Cancer Letters, 2024: 216706.
[23] KAUR P, VERMA S, KUSHWAHA P P, et al.EZH2 and NF-κB: A context-dependent crosstalk and transcriptional regulation in cancer[J]. Cancer Letters, 2023, 560: 216143.
[24] HAO A, WANG Y, STOVALL D, et al.Emerging Roles of LncRNAs in the EZH2-regulated Oncogenic Network.[J]. Int J Biol Sci, 2021, 17(13): 3268-3280.
[25] WANG S, XU L, WANG D, et al.YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation[J]. Cancer Letters, 2024, 597: 217047.
[26] WANG J, SHEN S, YOU J, et al.PRMT6 facilitates EZH2 protein stability by inhibiting TRAF6-mediated ubiquitination degradation to promote glioblastoma cell invasion and migration[J]. Cell Death Dis, 2024, 15(7): 524-536.
[27] WANG H, LIU Y, DING J, et al.Targeting mTOR suppressed colon cancer growth through 4EBP1/eIF4E/PUMA pathway[J]. Cancer Gene Ther, 2020, 27(6): 448-460.
[28] LI B B, QIAN C, GAMEIRO P A, et al.Targeted profiling of RNA translation reveals mTOR-4EBP1/2-independent translation regulation of mRNAs encoding ribosomal proteins[J]. Proc Natl Acad Sci U S A, 2018, 115(40): E9325-E9332.