Kdm6a and Kdm6b: Altered expression in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes. As such these genes could potentially represent novel candidate targets for intervention in MPM. Using RT-PCR we examined the expression of Kdm6aA and Kdm6b in a panel of MPM cell lines and in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic and sarcomatoid histologies. Both Kdm6a and Kdm6b were found to be significantly overexpressed in MPM at the mRNA level. However, tests examining if targeting therapeutically Kdm6a/b using a specific small molecule inhibitor (GSK-J4) was potentially useful for treating MPM, revealed that anti-proliferative activity was higher at lower drug concentrations in cell lines derived from normal mesothelial cells compared to those derived from malignant cells. Treatments with GSK-J4 were found to be associated with the induction of apoptosis and increased expression of pro-inflammatory cytokines. As such our results demonstrate that whilst members of the Kdm6 family are overexpressed in MPM they may not be suitable candidates for therapy and may elicit a cytokine storm.

Differences in gene expression despite identical histomorphology in sinonasal intestinal‐type adenocarcinoma and metastases from colorectal adenocarcinoma

“…Several of the genes upregulated in sITAC are involved in invasive properties also consistent with the differences in sITAC and CRC tumor behavior. KDM6A, which is a tumor suppressor via an interaction with the Retinoblastoma (Rb) gene [31][32][33], was upregulated in sITAC. Knockdown of KDM6A in colorectal cancer cells has been shown to reduce expression of E-cadherin mRNA, a hallmark of EMT in cancer progression, and overexpression of KDM6A can inhibit migration and invasion in vitro [32,34,35].…”

Targeting P16INK4A in uterine serous carcinoma through inhibition of histone demethylation

“…The third controversial issue is about the concentration of GSK-J4 (30 µM), which was a slightly increased, compared with other common small molecular inhibitors. However, this concentration had been frequently used in a number of studies on cervical cancer (11), brain glioma (34) and immunologic diseases (36,37), demonstrating that this concentration of GSK-J4 exerted prominent in vitro and in vivo anti-proliferative effects on cancerous and non-cancerous cells and tissues.…”

KDM6 Demethylases and Their Roles in Human Cancers

“…GSK-J4 are relatively unspecific as it also inhibits KDM5 subfamily in vitro (142). GSK-J4 has nevertheless been proposed for application in several cancer types, particularly in vivo of acute myeloid leukemia, breast cancer, TAL1 positive T-ALL, colorectal cancer and osteosarcoma (Table 2) (74,78,93,99,106,(131)(132)(133)(134)(135)(136)(137). These indicate that GSK-J4 might be a promising treatment for clinical cancer therapy.…”