Abstract:Upregulated expression of histone H3K4 demethylase JARID1B has been found in several types of human cancer, but the expression pattern of this protein in benign naevi and human cutaneous melanomas seems to differ from that described for other tumors. We demonstrate that the apparent contradiction may be because of the fact that the malignant transformation of melanocytes is associated not so much with a general enhancement of a total expression of JARID1B but rather with a change in relative expression levels … Show more
“…2a ). Such results suggest dominating contribution of the RBP2-H1 to intratumoral expression of the JARID1B protein and fully agree with our earlier observations [ 20 ]. Fig.…”
Section: Resultssupporting
confidence: 93%
“…Although JARID1B as a functional histone demethylase should be localized to nuclei the staining was either nuclear or both nuclear and cytoplasmic. Similar staining patterns were, however, observed also in earlier studies [ 11 , 12 , 18 , 20 ]. The mean percentage fractions of the cells stained for RBP2-H1 were only slightly lower than the fractions of the cells with the staining positive for the expression of all the three isoforms of JARID1B (Fig.…”
Section: Resultssupporting
confidence: 91%
“…Immunohistochemical studies involving relatively large sample of human melanomas [ 14 ] demonstrated that both primary and metastatic melanomas expressed higher levels of JARID1B compared to benign naevi. In our recent study [ 20 ] the expression of JARID1B was detected using two types of primary antibodies specific either to the total JARID1B protein or only to its RBP2-H1 isoform. The results indicated that malignant transformation of melanocytes is associated not so much with enhancement of the total JARID1B expression but rather with a change of the expression pattern of its isoforms with a significant increase of intratumoral expression of the RBP2-H1 variant in melanomas compared to naevi.…”
Section: Discussionmentioning
confidence: 99%
“…Expression of JARID1B was detected according to the protocols described in our previous paper [ 20 ]. Briefly the 3 μm sections were mounted on 3-aminopropyltriethoxysilane (Sigma-Aldrich, St. Louis, Missouri, USA) coated slides.…”
Section: Methodsmentioning
confidence: 99%
“…Our recent work [ 20 ] demonstrated for the first time that development of melanoma is associated rather with a change in relative expression levels of individual isoforms of JARID1B and not with enhancement of a total intratumoral expression of the protein. The RBP2-H1 variant was expressed by 75% of the cells of primary melanomas and 85% of the cells of metastatic lesions while in benign naevi its expression could be detected only in 25% of the cells.…”
BackgroundHistone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients’ prognosis have been reported.MethodsWe investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients.ResultsExpression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients.ConclusionsSuch results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3836-x) contains supplementary material, which is available to authorized users.
“…2a ). Such results suggest dominating contribution of the RBP2-H1 to intratumoral expression of the JARID1B protein and fully agree with our earlier observations [ 20 ]. Fig.…”
Section: Resultssupporting
confidence: 93%
“…Although JARID1B as a functional histone demethylase should be localized to nuclei the staining was either nuclear or both nuclear and cytoplasmic. Similar staining patterns were, however, observed also in earlier studies [ 11 , 12 , 18 , 20 ]. The mean percentage fractions of the cells stained for RBP2-H1 were only slightly lower than the fractions of the cells with the staining positive for the expression of all the three isoforms of JARID1B (Fig.…”
Section: Resultssupporting
confidence: 91%
“…Immunohistochemical studies involving relatively large sample of human melanomas [ 14 ] demonstrated that both primary and metastatic melanomas expressed higher levels of JARID1B compared to benign naevi. In our recent study [ 20 ] the expression of JARID1B was detected using two types of primary antibodies specific either to the total JARID1B protein or only to its RBP2-H1 isoform. The results indicated that malignant transformation of melanocytes is associated not so much with enhancement of the total JARID1B expression but rather with a change of the expression pattern of its isoforms with a significant increase of intratumoral expression of the RBP2-H1 variant in melanomas compared to naevi.…”
Section: Discussionmentioning
confidence: 99%
“…Expression of JARID1B was detected according to the protocols described in our previous paper [ 20 ]. Briefly the 3 μm sections were mounted on 3-aminopropyltriethoxysilane (Sigma-Aldrich, St. Louis, Missouri, USA) coated slides.…”
Section: Methodsmentioning
confidence: 99%
“…Our recent work [ 20 ] demonstrated for the first time that development of melanoma is associated rather with a change in relative expression levels of individual isoforms of JARID1B and not with enhancement of a total intratumoral expression of the protein. The RBP2-H1 variant was expressed by 75% of the cells of primary melanomas and 85% of the cells of metastatic lesions while in benign naevi its expression could be detected only in 25% of the cells.…”
BackgroundHistone demethylase JARID1B plays several context dependent roles in epigenetic regulation of cellular differentiation in normal development and is highly expressed in multiple human cancers. The protein is a strong transcriptional repressor capable of downregulating numerous genes. There are three splicing isoforms of JARID1B, however the links between the protein structure and function are not clear. The expression pattern of JARID1B in human melanoma seems to be different from observed in other cancers. Moreover, up to now no data on the impact of JARID1B expression in cutaneous melanoma on the patients’ prognosis have been reported.MethodsWe investigated immunohistochemically the association of intratumoral expression of total JARID1B protein and its RBP2-H1 isoform in primary and metastatic melanomas with prognosis for the patients.ResultsExpression of both total JARID1B protein and its RBP2-H1 variant was found in all the melanomas investigated. Our results indicate, however, that only high (above 90% of the cells) intratumoral expression of RBP2-H1 can be considered prognostic factor associated with worse overall survival of the patients.ConclusionsSuch results if considered together with data demonstrating a switch to enhanced expression of RBP2-H1 at early stages of malignant transformation of melanocytes are in agreement with hypothetical crucial role of JARID1B in the course of melanoma development and progression and suggest that altered splicing of JARID1B may be important factor increasing melanoma aggressiveness.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3836-x) contains supplementary material, which is available to authorized users.
KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the specific context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows a much faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and -gamma response. We discuss the relevance of this finding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.
KDM5B histone demethylase is overexpressed in many cancers and plays an ambivalent role in oncogenesis, depending on the specific context. This ambivalence could be explained by the expression of KDM5B protein isoforms with diverse functional roles, which could be present at different levels in various cancer cell lines. We show here that one of these isoforms, namely KDM5B-NTT, accumulates in breast cancer cell lines up to 50-60% of the total due to remarkable protein stability relative to the canonical PLU-1 isoform, which shows a much faster turnover. This isoform is the truncated and catalytically inactive product of an mRNA with a transcription start site downstream of the PLU-1 isoform, and the consequent usage of an alternative ATG for translation initiation. It also differs from the PLU-1 transcript in the inclusion of an additional exon (exon-6), previously attributed to other putative isoforms. Overexpression of this isoform in MCF7 cells leads to an increase in bulk H3K4 methylation and induces derepression of a gene cluster, including the tumor suppressor Cav1 and several genes involved in the interferon-alpha and -gamma response. We discuss the relevance of this finding considering the hypothesis that KDM5B may possess regulatory roles independent of its catalytic activity.
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