Loss of α6β4-dependent hemidesmosomal adhesions has been observed during prostate cancer progression. However, the significance and underlying mechanisms by which aberrant hemidesmosome assembly may modulate tumorigenesis remain elusive. Using an extensive CRISPR/Cas9-mediated genetic engineering approaches in different prostate cancer cell lines combined with in vivo tumorigenesis studies in mice, bone marrow-on-chip assays and bioinformatics, as well as histological analysis of prostate cancer patient cohorts, we demonstrated that simultaneous loss of PTEN and hemidesmosomal adhesions induced several tumorigenic properties including proliferation, migration, resistance to anoikis, apoptosis, and drug treatment in vitro, and increased metastatic capacity in vivo. These effects were plectin-depended and plectin was associated with actin-rich adhesions upon hemidesmosome disruption in PTEN-negative prostate cancer cells leading to activation of EGFR/PI3K/Akt- and FAK/Src-pathways. These results suggest that analysis of PTEN and hemidesmosomal proteins may have diagnostic value helping to stratify prostate cancer patients with high risk for development of aggressive disease and highlight actin-associated plectin as a potential therapeutic target specifically in PTEN/hemidesmosome dual-negative prostate cancer.

Hemidesmosomes (HDs) are adhesive structures that ensure stable anchorage of cells to the basement membrane. They are formed by α6β4-integrin heterodimers and linked to intermediate filaments via plectin. It has been reported that one of the most common events during the pathogenesis of prostate cancer (PCa) is the loss of HD organization. While the expression levels of β4-integrins are strongly reduced, the expression levels of α6-integrins and plectin are maintained or even elevated, and seem to promote tumorigenic properties of PCa cells, such as proliferation, invasion, metastasis, apoptosis- and drug-resistance. In this review, we discuss the potential mechanisms of how HD components might contribute to various cellular signaling pathways to promote prostate carcinogenesis. Moreover, we summarize the current knowledge on the involvement of α6β4-integrins and plectin in PCa initiation and progression.

Tankyrases establish an intricate network of protein interactions through their ankyrin repeat cluster domains (ARCs), which bind protein partners containing a characteristic peptide defined as a tankyrase‐binding motif (TBM). Once the protein complex has been formed, the proteins bound to ARCs can either undergo ADP‐ribosylation by tankyrases or stay unmodified. In the past years, this web of tankyrase‐centered interactions has grown as new partners have been discovered. Since the catalytic and scaffolding functions of tankyrases are extensively studied and tankyrases are targets for inhibition for therapeutic purposes, it is fundamental to explore and validate which proteins are regulated by tankyrases. In this study, we analyzed the tumor suppressor phosphatidylinositol 3,4,5‐trisphosphate 3‐phosphatase and dual‐specificity protein phosphatase PTEN as a previously reported tankyrase binding protein and substrate. Inhibition of tankyrase could stabilize PTEN, and this has been implied as a possible therapeutic strategy for using tankyrase inhibitors in cancer. However, we reveal that the described PTEN putative TBM (pTBM) does not bind tankyrase ARCs. This result is consistent with evolutionary analysis, which indicates that pTBM originated before tankyrases, unlike other validated TBMs. We employ pull‐down and ADP‐ribosylation assays to demonstrate that PTEN does not form a complex with tankyrase in vitro and that PTEN is not ADP‐ribosylated by tankyrase. Finally, we show that, in contrast to what was previously reported, catalytic inhibition of tankyrases does not have an impact on PTEN endogenous protein levels, excluding in this way any direct connection between PTEN and tankyrases.