Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer

Abstract

In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 kDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulphite-modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5 0 -azacytidine caused reexpression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer, 14/ 31 (45%), compared to adjacent nonmalignant or benign tissue, 2/19 (11%) (Po0.025). Immunohistochemistry showed a higher frequency of LDHB expression in benign or nonmalignant tissues, 59/ 73 (81%), compared to cancer cases, 3/53 (6%) (Po0.001). Absent LDHB expression was also seen in 7/7 (100%) cases of metastatic cancer in bone. Our data are the first to show loss of LDHB expression in prostate cancer, the mechanism of which appears to involve promoter hypermethylation.

Lactate Dehydrogenase B Is Required for the Growth of KRAS-Dependent Lung Adenocarcinomas

“…While an essential function of LDHA in tumor metabolism has been described (40), the role of LDHB is less clear. One report has shown that the mTOR pathway controls LDHB expression, whereas another report has shown that LDHB transcription is shut off by promoter methylation in bladder, colon, and prostate cancers (41)(42)(43)(44). In the context of lung adenocarcinoma, we observed that LDHB is upregulated in KRAS aberrant tumors and in a subset of cell lines containing other oncogenic drivers.…”

1009 Serum lactate dehydrogenase and survival following cancer diagnosis

“…It is known that the majority of LDH subunits detected in the serum is LDH-B, although LDH-A exists in a lesser amount (Maekawa, 1988). The absence of LDH-B expression and its enzyme activities have been reported in cell lines of breast , prostate (Leiblich et al, 2006), gastric and pancreatic cancer (Maekawa et al, 2003), suggested to be driven by promoter hypermethylation. As LDH-B kinetically favours the backward reaction of pyruvatelactate conversion (Augoff et al, 2014), this may suggest that LDH-A, which mostly catalyses the formation of lactate, is more relevant to cancer than LDH-B (Maekawa, 1988).…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…This relationship allows the tumor to take up lactate and to convert it to pyruvate, which is processed in the tricarboxylic acid cycle. However, opposing this model, prostate tumors overexpress lactate dehydrogenase A [129,[131][132][133], which preferentially works in the direction of lactate production [33,34]. Consistently, lactate dehydrogenase B, which catalyzes the lactate to pyruvate conversion, is suppressed [131,134].…”

“…However, opposing this model, prostate tumors overexpress lactate dehydrogenase A [129,[131][132][133], which preferentially works in the direction of lactate production [33,34]. Consistently, lactate dehydrogenase B, which catalyzes the lactate to pyruvate conversion, is suppressed [131,134]. This is further functionally supported by experiments with hyperpolarized pyruvate, where in situ tumors convert pyruvate into lactate [135][136][137].…”