Knockdown of FKBP3 suppresses nasopharyngeal carcinoma cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting histone deacetylase 2 expression

Jiadi Dong; Jingjing Chen; Qun Li; Shijie Qiu

doi:10.4103/cjop.CJOP-D-22-00075

ORIGINAL ARTICLE

Year : 2023 | Volume : 66 | Issue : 2 | Page : 85-92

Knockdown of FKBP3 suppresses nasopharyngeal carcinoma cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting histone deacetylase 2 expression

Jiadi Dong, Jingjing Chen, Qun Li, Shijie Qiu
Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, Zhejiang, China

Date of Submission	09-Aug-2022
Date of Decision	08-Nov-2022
Date of Acceptance	15-Nov-2022
Date of Web Publication	23-Feb-2023

Correspondence Address:
Dr. Shijie Qiu
Department of Otorhinolaryngology Head and Neck Surgery, Ningbo Medical Center Li Huili Hospital, Ningbo, No. 57, Xingning, Yinzhou
China

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/cjop.CJOP-D-22-00075

Abstract

Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor worldwide. FKBP3 has been reported to participate in tumorigenesis. Nevertheless, the role and mechanism of FKBP3 in NPC remains unclear. In this study, FKBP3 expression was observed to upregulate in NPC patients and cells. Moreover, knockdown of FKBP3 suppressed cell growth, invasion, and migration in HK1 and C666-1 cells. Mechanically, FKBP3 could enhance the p-p65 expression and activated p65 signaling pathway and increased interleukin-6 (IL-6) expression through enhancing histone deacetylase 2 (HDAC2) expression. In rescued experiment, the overexpression of HDAC2 restored diminished cell growth, invasion, and migration caused by FKBP3 depletion. In summary, the knockdown of FKBP3 suppressed NPC cell growth, invasion and migration, deactivated nuclear factor-κB/IL-6 signaling pathway through inhibiting HDAC2 expression, providing a potential therapeutic strategy for NPC treatment.

Keywords: Histone deacetylase 2, interleukin-6, invasion, migration, nasopharyngeal carcinoma, nuclear factor-κB

How to cite this article:
Dong J, Chen J, Li Q, Qiu S. Knockdown of FKBP3 suppresses nasopharyngeal carcinoma cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting histone deacetylase 2 expression. Chin J Physiol 2023;66:85-92

How to cite this URL:
Dong J, Chen J, Li Q, Qiu S. Knockdown of FKBP3 suppresses nasopharyngeal carcinoma cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting histone deacetylase 2 expression. Chin J Physiol [serial online] 2023 [cited 2023 May 29];66:85-92. Available from: https://www.cjphysiology.org/text.asp?2023/66/2/85/374406

Introduction

Nasopharyngeal carcinoma (NPC) is a special cancer caused by the epithelium of the nasopharynx. NPC is prevalent in South east Asia and Africa, especially in China, accounting for 40% of new cases globally each year.^[1],[2] Although radiation advances in NPC treatment, the cell growth, invasion, and migration remain to mainly lead treatment failure and cancer-related death.^[3] Indeed, approximately 30%–40% of patients develop distant metastases within 4 years, which predicts poor prognosis, mainly involving in chemical and radioresistant resistance.^[4] Hence, it is urgent to explore the mechanisms contributing to NPC progression and metastasis, which may help design more effective and targeted therapeutic strategies.

FKBP3 (also known as FKBP25) belongs to the FKBP family and is involved in tumor progression. It has been reported that FKBP3 acts a cancer-promoting role in breast cancer.^[5] Moreover, FKBP3 mediates oxaliplatin resistance and aggravated the colorectal cancer progression.^[6] Nevertheless, the investigations about the role of FKBP3 in NPC are extremely limited. Previously, FKBP3 locates in the nucleus and is associated with histone deacetylase 1/2 (HDAC1/2) activity.^[7] HDAC is an ancient enzyme superfamily that contains several members, containing HDAC1 and HDAC2, involving in tumorigenesis of diverse cancers.^[8] HDAC2 inhibits epithelial–mesenchymal transition (EMT)-mediated cancer metastasis by downregulating long non-coding RNA H19 in colorectal cancer.^[9] HDAC2 can increase the expression of interleukin-6 (IL-6) in osteosarcoma cells by activating nuclear factor-κB (NF-κB), thereby promoting cell migration.^[10] Interestingly, FKBP3 promotes lung cancer cells proliferation by regulating Sp1/HDAC2/p27 signaling.^[11] However, the relationship between FKBP3 and HDAC2 in NPC remains unclear.

NF-κB has crucial roles in cell proliferation, apoptosis, invasion and migration, which requires phosphorylation of NF-κB protein, p65.^[12] In this study, FKBP3 was found to be overexpressed in NPC cells, and knockdown of FKBP3 inhibited cell growth, invasion and migration of NPC cells, implying the vital role of FKBP3 in tumorigenesis of NPC.

Materials and Methods

Patient sample analysis

The RNA sequencing data of FKBP3 in NPC patients and normal subjects were obtained from The Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov/) database.

Cell culture and transfection

The nasopharyngeal epithelial cell line (NP-69) and NPC cell lines (HK1 and C666-1) were seeded in RPMI-1640 (Thermo Fisher Scientific, USA) medium containing 10% fetal bovine serum (FBS) (Thermo Fisher Scientific, USA) at 37°C in a humid chamber with 5% CO₂.

To establish knockdown of the FKBP3-expressing NPC cell lines, the HK1 and C666-1 cells were transfected with siFKB3#1, siFKB3#2 or their corresponding control siNC (Ribobio, China) by Lipofectamine 2000 (Invitrogen, USA). To establish overexpression of the FKBP3-expressing NPC cell lines, the HK1 and C666-1 cells were transfected with pcDNA3 (named NC) or pcDNA3-FKBP3 (named FKBP3) by Lipofectamine 2000.

For co-transfection, the HK1 and C666-1 cells were co-transfected with siNC or siFKB3#2 and pcDNA3-HDAC2 (named HDAC2) or pcDNA3 vector (named NC) by Lipofectamine 2000.

Colony formation assay

The cells after transfection (5 × 10³) were cultured in six-well plates for 2 weeks. Thereafter, the colonies in plates were stained by 1% crystal violet (Sigma-Aldrich, USA) and counted.

Cell counting kit-8 assay

A total of 4 × 10³ cells per well were added into 96 well plates. After incubating for 1, 3, and 5 days, the cells in each well were added with 10 μL of CCK-8 (Solarbio, China) and incubated for another 1 h. The absorbance value at 450 nm of each group was measured by a microplate reader (Biotek, USA).

Wound healing assay

The cells after transfection were seeded in 6 well plates and cultured in serum-free medium. The cells were scratched by a pipet tip. The wound area was observed at 0 h and 24 h under a light microscope (Leica, Germany) and then was measured by ImageJ software.

Transwell assay

The cells after transfection were seeded in the upper chamber supplemented with Matrigel. The lower chamber was filled with medium supplemented with 10% FBS. After 24 h, the nonmigratory cells were removed, and the invaded cells were fixed, stained with 1% crystal violet, and then visualized under a light microscope (Leica).

Enzyme-linked immunosorbent assay assay

IL-6 concentration in cultured supernatant was quantified by using the human IL-6 Enzyme-Linked Immunosorbent Assay (ELISA) Kit (Boster, China) according to the manufacturer's instructions. Besides, the matrix metalloproteinase 2 (MMP2) and MMP9 activities were evaluated by the ELISA kits (Abcam, UK), respectively.

Quantitative reverse transcription polymerase chain reaction

Total RNA was collected from the cells by TRIzol® (Invitrogen, USA) and reverse-transcribed into cDNA by the reverse transcription system (Promega, USA). Consequently, the quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed by SYBRPremix Ex TaqTM II (Takara, Japan). GAPDH was served as the normalization controls of mRNAs. The relative mRNA levels of target genes through 2^-ΔΔCT method. Primer sequences were as follows: FKBP3-forward: 5'-ACCCAAAGAAACCAAGTC-3' and FKBP3-reverse: 5'-ATACCAGCAGTGAACAAC-3'; IL-6-forward: 5'-ACTCACCTCTTCAGAACGAATTG-3' and IL-6-reverse: 5'-CCATCTTTGGAAGGTTCAGGTTG-3'; GAPDH-forward: 5'-AATCCCATCACCATCTTC-3' and GAPDH-reverse, 5'-AGGCTGTTGTCATACTTC-3'.

Western blot

Protein from all the cells was extracted, quantified by BCA kit (Beyotime, China), performed by electrophoresis, and then transferred onto PVDF membranes. Through blocked by skim milk, the membranes were incubated with FKBP3 antibody (1/700; Abcam, UK), N-cadherin antibody (1/700; Abcam, UK), E-cadherin antibody (1/700; Abcam, UK), MMP2 antibody (1/700; Abcam, UK), MMP9 antibody (1/700; Abcam, UK), HDAC2 antibody (1/700; Abcam, UK), p-p65 antibody (1/700; Abcam, UK), p65 antibody (1/700; Abcam, UK), or GAPDH antibody (1/700; Abcam, UK) overnight at 4°C. Followed by the incubation with proper secondary antibodies (1/5000; Abcam, UK) at room temperature for 1 h, the membrane was visualized by BeyoECL Plus kit (Beyotime, China).

Statistical analysis

All results in this study were expressed as means ± standard deviation and analyzed by the Student's t-tests or one-way analysis of variance through the analysis of GraphPad Prism 7.0 software. The P < 0.05 was supposed as statistical significance.

Results

FKBP3 expression was elevated in nasopharyngeal carcinoma patients and cells

The expression profile of FKBP3 in NPC patients and normal subjects was downloaded from TCGA database, implying that FKBP3 was significantly up-regulated in NPC patients compared to normal subjects. More importantly, the data from TCGA patients were analyzed by Ualcan database (ualcan.path.uab.edu), implying that FKBP3 expression was associated with tumor grade but was not related to age and tumor stages [Figure 1]a. Besides, the PrognoScan database (http://dna00.bio.kyutech.ac.jp/PrognoScan/index.html) predicted that high FKBP3 expression predicted a poor prognosis in NPC patients [Figure 1]b. In addition, FKBP3 mRNA level was dramatically enhanced in NPC cell lines, including HK1 and C666-1 [Figure 1]c. Consistently, western blot showed that higher FKBP3 expression was observed in C666-1 cells and HK1 cells than in NP69 cells [Figure 1]d. Therefore, these findings concluded that FKBP3 expression was elevated in NPC patients and cells.

Figure 1: FKBP3 expression was elevated in NPC patients and cells. (a) Enhanced expression of FKBP3 mRNA level in NPC tissues compared to normal subjects (normal = 44 and primary tumor = 520). The Ualcan database (ualcan.path.uab.edu) analyzed that FKBP3 expression was associated with tumor grade, but was not related to age and tumor stages. (b) PrognoScan database (http://dna00.bio.kyutech.ac.jp/PrognoScan/index.html) predicted that high FKBP3 expression predicted poor prognosis in NPC patients. (c) The FKBP3 mRNA level in nasopharyngeal epithelial cell line (NP-69) and NPC cell lines (HK1 and C666-1) were detected by qRT-PCR. (d) The protein level of FKBP3 in NP-69, HK1, and C666-1 cells. Each experiment repeated three times. **P < 0.01, ***P < 0.001. NPC: Nasopharyngeal carcinoma, qRT-PCR: Quantitative reverse transcription polymerase chain reaction.

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Knockdown of FKBP3 inhibited nasopharyngeal carcinoma cells growth in vitro

To explore the effect of FKBP3 on NPC cell growth, the efficiency of overexpression or silencing of FKBP3 was detected by the western blotting. FKBP3 was efficiently overexpress or knockdown in HK1 and C666-1 cells after transfection [Figure 2]a. From the results of CCK-8 and colony formation assays, both the HK1 and C666-1 cell lines showed significant decreases in cell viability and clonogenicity compared to controls as a consequence of the down-regulation of FKBP3. In contrast, overexpression of KBP3 was shown to promote cell proliferation and colony formation capabilities [Figure 2]b and [Figure 2]c. Thus, these results revealed that knockdown of FKBP3 inhibited NPC cells growth in vitro.

Figure 2: Knockdown of FKBP3 inhibited NPC cells growth in vitro. The HK1 and C666-1 cells were transfected with siFKBP3#1, siFKBP3#2 or FKBP3 to knockdown or overexpress FKBP3 in NPC cell lines. (a) The transfection efficiency of FKBP3 was detected by the western blot. (b) The cell viability was determined by CCK-8 assay. (c) The cell proliferation was evaluated by colony formation assay. Each experiment repeated three times. **P < 0.01, ***P < 0.001 versus siNC. ^^P < 0.01, ^^^P < 0.001 versus NC. NPC: Nasopharyngeal carcinoma.

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Knockdown of FKBP3 suppressed nasopharyngeal carcinoma invasion and migration in vitro

To verify the effects of FKBP3 on NPC cell invasion and migration, the wound healing and transwell assays were performed. As shown in [Figure 3]a and [Figure 3]b, the HK1 and C666-1 cells showed a significant increase in the cell migration rate following FKBP3 transfection, which manifested a diminished migration rate after FKBP3 depletion. Moreover, the transwell assay confirmed that the number of invasive NPC cells was promoted by upregulation of FKBP3, which was reduced by downregulation of FKBP3 [Figure 3]c and [Figure 3]d. Furthermore, western blot experiments confirmed that FKBP3 transfection resulted in downregulation of E-cadherin and up-regulation of N-cadherin, MMP2, and MMP9 in HK1 and C666-1 cells. On the other hand, the depletion of FKBP3 in the HK1 and C666-1 cells stimulated the up-regulation of E-cadherin and caused the downregulation of N-cadherin, MMP2, and MMP9 expression [Figure 3]e. Consistently, MMP2 and MMP9 concentrations were elevated in response to overexpression of FKBP3, which were reduced in response to knockdown of FKBP3 [Figure 3]f. Conversely, knockdown of FKBP3 suppressed NPC invasion and migration in vitro.

Figure 3: Knockdown of FKBP3 suppressed NPC invasion and migration in vitro. (a and b) The cell migration capability of HK1 and C666-1 cells was determined by wound healing assay. (c and d) The invasion capability of HK1 and C666-1 cells was detected by transwell assay. (e) The related proteins expression were evaluated by western blot, including MMP2, MMP9, E-cadherin and N-cadherin. (f) The concentrations of MMP2 and MMP9 were assessed by ELISA kits, respectively. Each experiment repeated three times. *P < 0.05, **P < 0.01, ***P < 0.001 versus siNC. ^P < 0.05, ^^P < 0.01, ^^^P < 0.001 versus NC. NPC: Nasopharyngeal carcinoma.

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FKBP3 activated p65/interleukin-6 signaling pathway through enhancing histone deacetylase 2 expression in nasopharyngeal carcinoma cells

It has been reported that FKBP3 promotes cancer cells proliferation through modulating HDAC2 expression.^[11] Interestingly, the results from the western blot showed that overexpression of enhanced HDAC2 and p-p65 expression, indicating the activation of p65 signaling pathway [Figure 4]a. Furthermore, we found that upregulation of FKBP3 promoted IL-6 mRNA level and concentration in HK1 and C666-1 cells [Figure 4]b and [Figure 4]c. In contrast, silencing of FKBP3 reduced HADC2 and p-p65 expression, which was reversed by the overexpression of HDAC2, indicating that FKBP3 activated p65 signaling pathway via enhancing HDAC2 expression [Figure 4]d. More importantly, knockdown of FKBP3 decreased IL-6 mRNA level and concentration in HK1 and C666-1 cells [Figure 4]e and [Figure 4]f. Thus, these findings revealed that FKBP3 activated p65/IL-6 signaling pathway through enhancing HDAC2 expression in NPC cells.

Figure 4: FKBP3 activated p65/IL-6 signaling pathway via enhancing HDAC2 expression in NPC cells. (a) The expression p-p65, p65 and HDAC2 were examined by western blot. (b and c) The mRNA level and concentration of FKBP3 were determined by qRT-PCR and commercial ELISA kit. (d) Through overexpressing HDAC2 in knockdown FKBP3 cells, the expression of p-p65, p65, and HDAC2 was detected by western blot. (e and f) The mRNA level and concentration of FKBP3 were determined by qRT-PCR and commercial ELISA kit. Each experiment repeated three times. *P < 0.05, **P < 0.01, ***P < 0.001. ^P < 0.05, ^^P < 0.01, ^^^P < 0.001 versus siFKBP3. NPC: Nasopharyngeal carcinoma, qRT-PCR: Quantitative reverse transcription polymerase chain reaction.

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Knockdown of FKBP3 suppressed nasopharyngeal carcinoma cell growth, invasion and migration via reducing histone deacetylase 2 expression

To estimate whether FKBP3 modulated NPC cell growth, invasion, and migration through reducing HDAC2 expression, the HDAC2 was overexpressed in NPC cells transfected with siFKBP3. As [Figure 5]a illustrated, upregulation of HDAC2 enhanced the decreased cell viability caused by siFKBP3 in HK1 and C666-1 cells. Moreover, overexpression of HDAC2 restored the diminished migration after FKBP3 depletion in NPC cells [Figure 5]b. Furthermore, the increase of HDAC2 expression significantly reversed the decreased NPC cell invasive number in HK1 and C666-1 cells [Figure 5]c. In conclusion, knockdown of FKBP3 suppressed NPC cell growth, invasion, and migration through reducing HDAC2 expression.

Figure 5: Knockdown of FKBP3 suppressed NPC cell growth, invasion and migration via reducing HDAC2 expression. The HK1 and C666-1 cells were co-transfected with siNC or siFKB3#2 and pcDNA3-HDAC2 (named HDAC2) or pcDNA3 vector (named NC). (a) The cell viability was measured by CCK-8 assay. (b) The cell migration capability was determined by wound healing assay. (c) The cell invasion capability was detected by transwell assay. Each experiment repeated three times. **P < 0.01, ***P < 0.001 versus siNC + NC. ^^P < 0.01, ^^^P < 0.001 versus siFKBP3#2 + NC. NPC: Nasopharyngeal carcinoma.

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Discussion

In this study, FKBP3 expression was observed to upregulate in NPC patients and cells. Moreover, knockdown of FKBP3 suppressed cell growth, invasion, and migration in HK1 and C666-1 cells. Mechanically, FKBP3 could enhance the p-p65 expression and activated p65 signaling pathway and increased IL-6 expression via enhancing HDAC2 expression. In rescued experiment, overexpression of HDAC2 restored diminished cell growth, invasion, and migration caused by FKBP3 depletion. In summary, knockdown of FKBP3 suppressed NPC cell growth, invasion, and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting HDAC2 expression, providing a potential therapeutic strategy for NPC treatment.

Owing to the tumor recurrence and distant metastasis, the annual incidence of NPC has been increasing. FKBP3 is a novel protein and participated in multiple tumorigenesis. In lung cancer, upregulation of FKBP3 expression exerts proliferation-promoting effect and is associated with poor prognosis.^[11] In breast cancer, knockdown of FKBP3 inhibited proliferation and invasion and induced apoptosis.^[5] Nevertheless, the expression and role of FKBP3 in NPC remains unknown. In the present study, we demonstrated that FKBP3 was up-regulated in NPC patients and cells. Mechanically, knockdown of FKBP3 suppressed cell growth, invasion, and migration in NPC cells, which was highly consistent with previous studies. Nevertheless, the pro-proliferation, pro-invasion, and pro-migration effects of FKBP3 should be explored further. It has previously been reported that FKBP3 can modulate the activity of HDAC2 through regulating histone acetylation.^[6],[7] Zhu et al. have demonstrated the interaction between FKBP3 and HDAC2, since FKBP3 knockdown reduced HDAC2 expression but induced p27 expression.^[11] Similarly, our findings supported that knockdown of FKBP3 reduced HDAC2 expression in NPC cells, while overexpression of HDAC2 could abolished the suppressive effects of siFKBP3 on NPC cell growth, migration, and invasion, implying that knockdown of FKBP3 suppressed NPC cells growth, migration, and invasion through reducing HDAC2 expression.

Interestingly, NF-κB acts as an activator of the metastasis process to aggravate tumor progression, which is commonly activated in NPC.^[13] It is well accepted that p65 signaling pathway has important roles in carcinogenesis.^[14] Aberrant activation of p65 signaling leads to abnormal regulation of proliferation, invasion and migration.^[15] Once p65 signaling pathway is activated, the p65/p50 heterodimer translocates into the nucleus and modulates the downstream NF-κB signaling pathway.^[16] In the current study, FKBP3 enhanced the phosphorylation of p65, indicating the activation of p65 signaling pathway. Furthermore, we demonstrated that overexpression of HDAC2 abolished the impact of siFKBP3 on deactivation of p65/NF-κB signaling pathway, indicating that depletion of FKBP3 deactivated p65/NF-κB signaling pathway via reducing HDAC2 expression.

It is well illustrated that the expression of IL-6 is modulated by NF-κB signaling pathway in cancer cells through directly binding to the promoter of IL-6.^[17] HDAC2 mediates upregulation of IL-6 and triggers the cell migration.^[10] Indeed, the level of IL-6 is closely related to the pathogenesis and progression of NPC. IL-6 has been shown to enhance proliferation and invasion of NPC cells through modulating STAT3 signaling pathway.^[18] Besides, it has been demonstrated that IL-6 promoted invasion and migration of NPC cells by promoting MMP2 and MMP9 expression.^[19] Nowadays, we demonstrated that overexpression of HDAC2 rescued the low level of IL-6 caused by knockdown of FKBP3, indicating that knockdown of FKBP3 suppressed IL-6 signaling pathway through reducing HDAC2 expression. Notably, HDAC2 can interact with EZH2 to inhibit cell invasive capability and E-cadherin expression, which support our results that knockdown of FKBP3 decreased HDAC2 but increased E-cadherin expression.^[10] Nevertheless, there are still limitations in this study. First, it could not be excluded that whether other mechanisms might contribute to FKBP3-promoted NPC invasion and migration. Next, given that IL-6 can promote cell invasion and migration through modulating STAT3 signaling pathway, whether FKBP3 can modulate STAT3 signaling pathway remains unclear, which might be an interesting topic for another story in the future.^[20]

Conclusion

In summary, our results demonstrate a mechanism whereby knockdown of FKBP3 suppresses NPC cell growth, invasion and migration, deactivated NF-κB/IL-6 signaling pathway through inhibiting HDAC2 expression, providing a potential therapeutic strategy for NPC treatment.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Financial support and sponsorship

This work was supported by the Ningbo Medical and Health Brand Discipline (Grant No. PPXK2018-02).

Conflicts of interest

There are no conflicts of interest.

References

1.	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
2.	Chen YP, Chan AT, Le QT, Blanchard P, Sun Y, Ma J. Nasopharyngeal carcinoma. Lancet 2019;394:64-80.
3.	Wang Y, Chen W, Lian J, Zhang H, Yu B, Zhang M, et al. The lncRNA PVT1 regulates nasopharyngeal carcinoma cell proliferation via activating the KAT2A acetyltransferase and stabilizing HIF-1α. Cell Death Differ 2020;27:695-710.
4.	Lee AW, Ng WT, Chan JY, Corry J, Mäkitie A, Mendenhall WM, et al. Management of locally recurrent nasopharyngeal carcinoma. Cancer Treat Rev 2019;79:101890.
5.	Liu P, Xie X, Yang A, Kong Y, Allen-Gipson D, Tian Z, et al. Melatonin regulates breast cancer progression by the lnc010561/miR-30/FKBP3 axis. Mol Ther Nucleic Acids 2020;19:765-74.
6.	Tong J, Shen Y, Chen X, Wang R, Hu Y, Zhang X, et al. FKBP3 mediates oxaliplatin resistance in colorectal cancer cells by regulating HDAC2 expression. Oncol Rep 2019;42:1404-12.
7.	Yang WM, Yao YL, Seto E. The FK506-binding protein 25 functionally associates with histone deacetylases and with transcription factor YY1. EMBO J 2001;20:4814-25.
8.	Oiso H, Furukawa N, Suefuji M, Shimoda S, Ito A, Furumai R, et al. The role of class I histone deacetylase (HDAC) on gluconeogenesis in liver. Biochem Biophys Res Commun 2011;404:166-72.
9.	Hu XT, Xing W, Zhao RS, Tan Y, Wu XF, Ao LQ, et al. HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer. J Exp Clin Cancer Res 2020;39:270.
10.	Li J, Yan X, Tang J, Wang Y, Tang J, Wu W, et al. HDAC2-mediated upregulation of IL-6 triggers the migration of osteosarcoma cells. Cell Biol Toxicol 2019;35:423-33.
11.	Zhu W, Li Z, Xiong L, Yu X, Chen X, Lin Q. FKBP3 promotes proliferation of non-small cell lung cancer cells through regulating Sp1/HDAC2/p27. Theranostics 2017;7:3078-89.
12.	Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: Implications in cancer and inflammation. Trends Biochem Sci 2005;30:43-52.
13.	Bruce JP, To KF, Lui VW, Chung GT, Chan YY, Tsang CM, et al. Whole-genome profiling of nasopharyngeal carcinoma reveals viral-host co-operation in inflammatory NF-κB activation and immune escape. Nat Commun 2021;12:4193.
14.	Karin M. Nuclear factor-kappaB in cancer development and progression. Nature 2006;441:431-6.
15.	Liang Y, Feng G, Wu L, Zhong S, Gao X, Tong Y, et al. Caffeic acid phenethyl ester suppressed growth and metastasis of nasopharyngeal carcinoma cells by inactivating the NF-κB pathway. Drug Des Devel Ther 2019;13:1335-45.
16.	Chen S, Jiang S, Zheng W, Tu B, Liu S, Ruan H, et al. RelA/p65 inhibition prevents tendon adhesion by modulating inflammation, cell proliferation, and apoptosis. Cell Death Dis 2017;8:e2710.
17.	He G, Karin M. NF-κB and STAT3 – Key players in liver inflammation and cancer. Cell Res 2011;21:159-68.
18.	Zhang X, Yang J, Bian Z, Shi D, Cao Z. Long noncoding RNA DANCR promotes nasopharyngeal carcinoma progression by interacting with STAT3, enhancing IL-6/JAK1/STAT3 signaling. Biomed Pharmacother 2019;113:108713.
19.	Zeng J, Chen S, Li C, Ye Z, Lin B, Liang Y, et al. Mesenchymal stem/stromal cells-derived IL-6 promotes nasopharyngeal carcinoma growth and resistance to cisplatin via upregulating CD73 expression. J Cancer 2020;11:2068-79.
20.	Yang X, Gong J, Cai X, Yuan Y. Overexpression of HIC1 plays a protective effect on renal cell injury caused by lipopolysaccharide by inhibiting IL-6/STAT3 pathway. Signa Vitae 2022;18:147-53.