The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma

Abstract

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. Significance: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway. See related commentary by Brekken, p. 1624

Loss of BAP1 Leads to More YAPing in Pancreatic Cancer

“…Consistent with this, YAP and TAZ, the two major effectors of the Hippo pathway, have been shown to be significantly elevated in human PDAC (7). Lee and colleagues (5) found that loss of Bap1 resulted in elevation of Yap and Taz and canonical target genes Cyr61 (Ccn1) and Ctgf (Ccn2) in tumor tissue and tumor cells derived from the Kras-driven mouse tumors. Importantly, they also found that loss of Bap1 resulted in sensitivity of PDAC cells to knockdown of Yap/Taz.…”

Post-Translational Modifications of Deubiquitinating Enzymes: Expanding the Ubiquitin Code

“…However, when ubiquitination occurs on JosD1, it tends to localize on the cell membrane (Figure 2B) and plays a vital role in membrane dynamics, cell motility, and endocytosis (Seki et al, 2013;Zeng et al, 2020). Furthermore, BAP1, a member of the UCHs subfamily, is predominantly located in the nucleus and functions as a tumour suppressor (Cheung and Testa, 2017;Lee et al, 2020;Han et al, 2021). The lysine residues near the nuclear localization sequence (NLS) of BAP1 can be ubiquitinated, which leads to the accumulation of ubiquitinated BAP1 in the cytosol.…”

“…Furthermore, BAP1, a member of the UCHs subfamily, is predominantly located in the nucleus and functions as a tumour suppressor ( Cheung and Testa, 2017 ; Lee et al, 2020 ; Han et al, 2021 ). The lysine residues near the nuclear localization sequence (NLS) of BAP1 can be ubiquitinated, which leads to the accumulation of ubiquitinated BAP1 in the cytosol.…”

Regulation of metabolic reprogramming by tumor suppressor genes in pancreatic cancer

“…BAP1, also known as BRCA-associated protein 1, is a deubiquitinating enzyme that regulates various activities by forming multi-protein complexes. And it has been demonstrated that its mutation is associated with the initiation and development of multiple tumors including pancreatic cancer [89,90]. Recently, Lee et al demonstrated BAP1 exert a tumor suppressor function in pancreatic cancer by deubiquitinating LATS2 (large tumor suppressor, homolog 2), the negative regulator of Hippo pathway which could activate oncoproteins YAP and TAZ [89].…”

“…And it has been demonstrated that its mutation is associated with the initiation and development of multiple tumors including pancreatic cancer [89,90]. Recently, Lee et al demonstrated BAP1 exert a tumor suppressor function in pancreatic cancer by deubiquitinating LATS2 (large tumor suppressor, homolog 2), the negative regulator of Hippo pathway which could activate oncoproteins YAP and TAZ [89]. In terms of metabolism reprograming, Bononi et al found the aerobic glycolysis and lactate secretion are increased, while mitochondrial respiration and ATP production are reduced both in primary fibroblasts and human mesothelial cells when BAP1 was mutated or downregulated [91].…”