Research Article For reprint orders, please contact: [email protected]
Elevated expression of histone demethylase PHF8 associates with adverse prognosis in patients of laryngeal and hypopharyngeal squamous cell carcinoma Aim: Overexpression of histone demethylase PHF8 has been reported to function as an oncoprotein in many cancers; however, the implications of PHF8 involvement in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remain unclear. This study aims to explore the expression of PHF8 and its clinical significance in LHSCC. Materials & methods: Western blotting and immunohistochemistry were performed to evaluate PHF8 protein expression in fresh and archived LHSCC samples. Global expressions of H3K27 and H3K9 methylation were analyzed in a cell line with PHF8 siRNA treatment. Results & conclusion: In our study, PHF8 was upregulated in fresh LHSCC tissues. Immunohistochemical staining revealed that the expression of PHF8 was positively associated with T classification, clinical stage, primary tumor position and tumor relapse. Survival analysis demonstrated that high PHF8 expression was significantly associated with shorter overall survival and disease-free survival. Moreover, PHF8 regulates the levels of H3K9me2 and H3K27me2 in LHSCC. Taken together, PHF8 might be a novel prognostic marker for this disease. Keywords: epigenetic marker • H3K9 • H3K27 • histone demethylation • laryngeal and hypopharyngeal squamous cell carcinoma • metastasis • PHF8 • recurrence • squamous cell carcinoma of the head and neck • survival time
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most prevalent malignant neoplasm worldwide, with an incidence of approximately 650,000 new patients annually [1,2] . Despite refinements of examination procedures and improvements in comprehensive treatment over the last three decades, the overall 5-year survival rate of SCCHN patients has been constant at approximately 60% [3] . SCCHN consists of several cancers derived from distinct anatomic sites (e.g., lip, tongue, oral cavity, larynx and hypopharynx). Among these subtype cancers, laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) – consisting of the majority of cancers diagnosed at otorhinolaryngology department – makes up approximately 32.2% of SCCHNs [4] . Tumor metastasis or relapse, even after combined therapy, mainly results in a worse prognosis [5] . Interestingly, as a causative independent
10.2217/EPI.14.82 © 2015 Future Medicine Ltd
risk factor, human papillomavirus infection seems to have a favorable contribution to patient survival. For physicians, predicting patient outcomes and making therapeutic decisions based only on TNM classification (description of the size of the primary tumor and whether it has invaded nearby tissue, regional lymph nodes that are involved and distant metastasis) is a large limitation. Molecular tumor biomarkers facilitate the diagnosis and prognosis for SCCHN patients [6] . Therefore, it is expected that the identification of novel biomarkers will assist with improving patient care and survival. Histones, including H2A, H2B, H3 and H4, are a special group of nuclei proteins carrying the positively charged amino acids arginine and lysine, which easily bind to negatively charged DNA [7,8] . Aberrant expression of epigenetic targets in reversible histone modification is functionally corre-
Epigenomics (Epub ahead of print)
Gangcai Zhu1,2, Lijun Liu1,3, Li She1,2, Haolei Tan1,2, Ming Wei1,2, Changhan Chen1,2, Zhongwu Su1,2, Donghai Huang1,2, Yongquan Tian1,2, Yuanzheng Qiu1,2, Yong Liu*,1,2,‡ & Xin Zhang*,1,2,‡ 1 Department of Otolaryngology Head & Neck Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China 2 Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, Hunan, China 3 Department of Otolaryngology Head & Neck Surgery, First Affiliated Hospital of South China University, Chuanshan Road 69, Hengyang, 421001, China *Authors for correspondence: Tel.: +86 138 7315 8885 Fax: +86 731 8975 3045 xinzhang@ csu.edu.cn ‡ Authors contributed equally
part of
ISSN 1750-1911
Research Article Zhu, Liu, She et al.
Table 1. Correlations between PHF8 expression and clinicopathological variables in patients with laryngeal and hypopharyngeal squamous cell carcinoma. χ2 value
p-value
Low
21
24
0.017
1
50 (52.63)
24
26
Male
92 (96.84)
43
49
0.468
0.602
Female
3 (3.16)
2
1
No
42 (44.21)
20
22
0.002
1
Yes
53 (55.79)
25
28
No
28 (29.47)
13
15
0.014
1
Yes
67 (70.53)
32
35
2/3
30 (31.58)
11
19
2.035
0.188
1
65 (68.42)
34
31
Glottic
36 (37.89)
9
27
12.043
0.001
Others
59 (62.10)
36
23
T1 + T2
54 (56.84)
19
35
7.537
0.008
T3 + T4
41 (43.16)
26
15
I–II
43 (45.26)
15
28
4.965
0.039
III–IV
52 (54.74)
30
22
60 (63.16)
28
32
0.032
1
35 (36.84)
17
18
No
44 (46.32)
15
29
5.481
0.023
Yes
48 (50.53)
28
20
Variable
Number (%)
High
Elevated expression of histone demethylase PHF8 associates with adverse prognosis in patients of laryngeal and hypopharyngeal squamous cell carcinoma Aim: Overexpression of histone demethylase PHF8 has been reported to function as an oncoprotein in many cancers; however, the implications of PHF8 involvement in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) remain unclear. This study aims to explore the expression of PHF8 and its clinical significance in LHSCC. Materials & methods: Western blotting and immunohistochemistry were performed to evaluate PHF8 protein expression in fresh and archived LHSCC samples. Global expressions of H3K27 and H3K9 methylation were analyzed in a cell line with PHF8 siRNA treatment. Results & conclusion: In our study, PHF8 was upregulated in fresh LHSCC tissues. Immunohistochemical staining revealed that the expression of PHF8 was positively associated with T classification, clinical stage, primary tumor position and tumor relapse. Survival analysis demonstrated that high PHF8 expression was significantly associated with shorter overall survival and disease-free survival. Moreover, PHF8 regulates the levels of H3K9me2 and H3K27me2 in LHSCC. Taken together, PHF8 might be a novel prognostic marker for this disease. Keywords: epigenetic marker • H3K9 • H3K27 • histone demethylation • laryngeal and hypopharyngeal squamous cell carcinoma • metastasis • PHF8 • recurrence • squamous cell carcinoma of the head and neck • survival time
Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most prevalent malignant neoplasm worldwide, with an incidence of approximately 650,000 new patients annually [1,2] . Despite refinements of examination procedures and improvements in comprehensive treatment over the last three decades, the overall 5-year survival rate of SCCHN patients has been constant at approximately 60% [3] . SCCHN consists of several cancers derived from distinct anatomic sites (e.g., lip, tongue, oral cavity, larynx and hypopharynx). Among these subtype cancers, laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) – consisting of the majority of cancers diagnosed at otorhinolaryngology department – makes up approximately 32.2% of SCCHNs [4] . Tumor metastasis or relapse, even after combined therapy, mainly results in a worse prognosis [5] . Interestingly, as a causative independent
10.2217/EPI.14.82 © 2015 Future Medicine Ltd
risk factor, human papillomavirus infection seems to have a favorable contribution to patient survival. For physicians, predicting patient outcomes and making therapeutic decisions based only on TNM classification (description of the size of the primary tumor and whether it has invaded nearby tissue, regional lymph nodes that are involved and distant metastasis) is a large limitation. Molecular tumor biomarkers facilitate the diagnosis and prognosis for SCCHN patients [6] . Therefore, it is expected that the identification of novel biomarkers will assist with improving patient care and survival. Histones, including H2A, H2B, H3 and H4, are a special group of nuclei proteins carrying the positively charged amino acids arginine and lysine, which easily bind to negatively charged DNA [7,8] . Aberrant expression of epigenetic targets in reversible histone modification is functionally corre-
Epigenomics (Epub ahead of print)
Gangcai Zhu1,2, Lijun Liu1,3, Li She1,2, Haolei Tan1,2, Ming Wei1,2, Changhan Chen1,2, Zhongwu Su1,2, Donghai Huang1,2, Yongquan Tian1,2, Yuanzheng Qiu1,2, Yong Liu*,1,2,‡ & Xin Zhang*,1,2,‡ 1 Department of Otolaryngology Head & Neck Surgery, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha 410008, Hunan, China 2 Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, Hunan, China 3 Department of Otolaryngology Head & Neck Surgery, First Affiliated Hospital of South China University, Chuanshan Road 69, Hengyang, 421001, China *Authors for correspondence: Tel.: +86 138 7315 8885 Fax: +86 731 8975 3045 xinzhang@ csu.edu.cn ‡ Authors contributed equally
part of
ISSN 1750-1911
Research Article Zhu, Liu, She et al.
Table 1. Correlations between PHF8 expression and clinicopathological variables in patients with laryngeal and hypopharyngeal squamous cell carcinoma. χ2 value
p-value
Low
21
24
0.017
1
50 (52.63)
24
26
Male
92 (96.84)
43
49
0.468
0.602
Female
3 (3.16)
2
1
No
42 (44.21)
20
22
0.002
1
Yes
53 (55.79)
25
28
No
28 (29.47)
13
15
0.014
1
Yes
67 (70.53)
32
35
2/3
30 (31.58)
11
19
2.035
0.188
1
65 (68.42)
34
31
Glottic
36 (37.89)
9
27
12.043
0.001
Others
59 (62.10)
36
23
T1 + T2
54 (56.84)
19
35
7.537
0.008
T3 + T4
41 (43.16)
26
15
I–II
43 (45.26)
15
28
4.965
0.039
III–IV
52 (54.74)
30
22
60 (63.16)
28
32
0.032
1
35 (36.84)
17
18
No
44 (46.32)
15
29
5.481
0.023
Yes
48 (50.53)
28
20
Variable
Number (%)
High
