BOK displays cell death‐independent tumor suppressor activity in non‐small‐cell lung carcinoma

Abstract

Since the genomic region containing the Bcl-2-related ovarian killer (BOK) locus is frequently deleted in certain human cancers, BOK is hypothesized to have a tumor suppressor function. In the present study, we analyzed primary non-small cell lung carcinoma (NSCLC) tumors and matched lung tissues from 102 surgically treated patients. We show that BOK protein levels are significantly downregulated in NSCLC tumors as compared to lung tissues (P<0.001). In particular, we found BOK downregulation in NSCLC tumors of grades two (P=0.004, n=35) and three (P=0.031, n=39) as well as in tumors with metastases to hilar (pN1) (P=0.047, n=31) and mediastinal/subcarinal lymph nodes (pN2) (P=0.021, n=18) as opposed to grade one tumors (P=0.688, n=7) and tumors without lymph node metastases (P=0.112, n=51). Importantly, in lymph node positive patients, BOK expression greater than the median value was associated with longer survival (P=0.002, Mantel test). Using in vitro approaches, we provide evidence that BOK overexpression is inefficient in inducing apoptosis but that it inhibits TGFβ-induced migration and epithelial-to-mesenchymal transition (EMT) in lung adenocarcinoma-derived A549 cells. We have identified epigenetic mechanisms, in particular BOK promoter methylation, as an important means to silence BOK expression in NSCLC cells. Taken together, our data point toward a novel mechanism by which BOK acts as a tumor suppressor in NSCLC by inhibiting EMT. Consequently, the restoration of BOK levels in low-BOK-expressing tumors might favor the overall survival of NSCLC patients.

Targeting BCL-2 regulated apoptosis in cancer

“…Using chimeric mice Bax/Bak deletion in the haematopoietic compartment drives fatal autoimmune disease [ 110 ]. The prominence of autoimmune disease in chimeric mice with Bax/Bak [ 111 ] deficient haematopoietic systems may mask tumour development. Targeted deletion mouse studies can avoid these autoimmune complications and in this setting loss of BAX/BAK in the brain and testicles results in tumours [ 112 ].…”

“…It seems pertinent loss of Bok is a relatively frequent event in a range of cancers [ 76 ] and gene silencing may result in loss of BOK protein in additional cases [ 111 ]. BOK is downregulated in non-small cell lung cancer (NSCLC) and high BOK is associated with good prognosis in lymph-node positive patients [ 111 ].…”

“…It seems pertinent loss of Bok is a relatively frequent event in a range of cancers [ 76 ] and gene silencing may result in loss of BOK protein in additional cases [ 111 ]. BOK is downregulated in non-small cell lung cancer (NSCLC) and high BOK is associated with good prognosis in lymph-node positive patients [ 111 ]. Interestingly, the tumour suppressive effect of BOK in NSCLC does not seem to be through apoptotic regulation and is instead through antagonism of TGF-β2 mediated epithelial to mesenchymal transition (EMT) and cell migration [ 111 ].…”

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

“…However, BOK deficient mice show no overt phenotypic changes and cells derived from these mice are not hampered in apoptosis [81]. Several studies suggest that BOK exerts its anti-tumorigenic effects through non-apoptotic functions [82,83]. On the other hand, a pro-tumorigenic role for BOK is reported in hepatocellular carcinoma where deletion of BOK is infrequent [84].…”

BOK (BCL2 family apoptosis regulator BOK)

“…These results support the favorable prognostic value of BOK in NSCLC patients. More specifically, there are indications that the BOK overexpression in NSCLC patients is associated with longer overall survival (Moravcikova et al, 2017).…”