Correspondence: On the enzymology and significance of HSPA1 lysine methylation.
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ABSTRACT:
SUBMITTER: Jakobsson ME
PROVIDER: S-EPMC4915027 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Correspondence: On the enzymology and significance of HSPA1 lysine methylation.
Jakobsson Magnus E ME Moen Anders A Falnes Pål Ø PØ
Nature communications 20160620
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Project description:Cellular proteins are subject to frequent methylation on lysine residues, introduced by specific methyltransferases, and each lysine residue can receive up to three methyl groups. Histone methylations, which are key determinants of chromatin state and transcriptional status, have been subject to particularly intense studies, but methylations on non-histone protein substrates are also abundant and biologically significant. Numerous studies have addressed lysine methylation in the realm of cancer biology. A recent study used an antibody-based approach to investigate the methylation of Lys-561 of the stress-inducible Hsp70 protein HSPA1, focusing exclusively on dimethylated HSPA1, concluding that it was elevated in cancer [Cho et al. (2012), Nat. Commun.,3, 1072]. In the present study, we have performed a more extensive analysis of HSPA1 methylation status in cancer samples, using protein mass spectrometry. We found that the four methylation states of Lys561 on HSPA1 (un-, mono-, di- and trimethylated) could be measured accurately and reproducibly in samples from carcinomas. We investigated HSPA1 methylation in 70 effusions, representing 53 high-grade serous ovarian carcinomas and 17 breast carcinomas. Notably, we found the trimethylated form of HSPA1 to be predominant in the cancer samples. HSPA1 methylation was studied for association with clinicopathologic parameters, including chemotherapy response and survival. The trimethylated form was more prevalent in breast carcinoma effusions (p = 0.014), whereas the dimethylated (p = 0.025), monomethylated (p = 0.004) and unmethylated (p = 0.021) forms were overrepresented in the ovarian carcinomas. For the ovarian carcinomas, the monomethylated (p = 0.028) and unmethylated (p = 0.007) forms were significantly related to the presence of higher residual disease volume, while the unmethylated form was significantly associated with poor overall (p = 0.015) and progression-free (p = 0.012) survival. In conclusion, lysine methylation of HSPA1 differs between metastatic breast and ovarian carcinoma, and unmethylated HSPA1 shows potential as a prognostic marker in high-grade serous carcinoma.
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Project description:Histone modifications of lysine residues have been implicated as having diagnostic and/or prognostic significance in numerous types of cancer. In the present study, the significance of the histone H3 methylation of lysine 4 (H3K4) and lysine 27 (H3K27) were investigated in endometrial cancer. Specifically, immunohistochemical analysis was used to detect the cellular expression levels of H3K27 trimethylation (H3K27me3), H3K4 trimethylation (H3K4me3) and H3K4 dimethylation (H3K4me2) in glandular epithelial tissues and stromal tissues. The association between the methylation levels of histone markers and clinicopathological parameters were analyzed. The results demonstrated that in epithelial cells, H3K4me2 and H3K4me3 exhibited the highest levels in endometrial cancer, followed by precancerous lesions and a normal endometrium. Low expression levels of H3K4me2 in glandular epithelium of endometrial cancer were significantly associated with a clinical early International Federation of Gynecology and Obstetrics stage (P=0.006). For stromal tissues, the expression level of H3K27me3 in Type 1 endometrial cancer was significantly lower compared with that in the normal endometrium (P=0.043) and precancerous lesions (P<0.001). The expression level of H3K4me2 was significantly lower in the stroma of Type 1 and 2 cancer compared within the normal endometrium (P=0.005). A low H3K4me3 expression level in the stroma of endometrial cancer tissues was associated with P53-negativity (P=0.032). In conclusion, the cellular expression levels of histone H3 methylation were differentially presented in glandular epithelial and stromal elements in endometrial tissues. A low expression level of activation marker H3K4me2 in glandular epithelium defined a subset of patients with early-stage endometrial adenocarcinoma and may have potential prognostic value.
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