Division of labor between YAP and TAZ in non-small cell lung cancer

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. The paralogous transcriptional cofactors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, also called WWTR1), the main downstream effectors of the Hippo signal transduction pathway, are emerging as pivotal determinants of malignancy in lung cancer. Traditionally, studies have tended to consider YAP and TAZ as functionally redundant transcriptional cofactors, with similar biological impact. However, there is growing evidence that each of them also possesses distinct attributes. Here, we sought to systematically characterize the division of labor between YAP and TAZ in non-small cell lung cancer (NSCLC), the most common histological subtype of lung cancer. Employing representative NSCLC cell lines, as well as patient-derived data, we show that the two paralogs orchestrate non-overlapping transcription programs in this cancer type: whereas YAP preferentially regulates gene sets associated with cell division and cell cycle progression, TAZ preferentially regulates genes associated with extracellular matrix organization. Concordantly, depletion of YAP, but not TAZ, leads to growth arrest, while YAP overexpression promotes cell proliferation. Likewise, depletion of TAZ, but not YAP, compromises cell migration, whereas TAZ overexpression enhances migration. Importantly, the differential effects of YAP vs TAZ on key cellular processes are also associated with differential response to anti-cancer therapies. Uncovering the different activities and downstream effects of YAP and TAZ may thus facilitate better stratification of lung cancer patients for anti-cancer therapies.

YAP and TAZ are transcriptional co-activators of AP-1 proteins and STAT3 during breast cellular transformation

“…Genetic experiments indicate that YAP and TAZ have distinct and overlapping cellular functions ( Plouffe et al, 2018 ; Shreberk-Shaked et al, 2020 ), but there is limited molecular understanding and no evidence for YAP- or TAZ-specific targets. Using two independent analyses, we identify 450 TAZ-specific target sites and 125 YAP-specific target sites in addition to the vastly larger number of shared YAP/TAZ sites.…”

“…YAP/TAZ activation is also linked to chemo-resistance in cancer therapy ( Johnson and Halder, 2014 ; Yu et al, 2015 ; Zanconato et al, 2016 ). Genetic experiments indicate that YAP and TAZ have distinct and overlapping cellular functions ( Plouffe et al, 2018 ; Shreberk-Shaked et al, 2020 ), but the molecular basis for the distinct functions is unknown. More generally, the transcriptional mechanisms and regulatory circuits mediated by YAP/TAZ in cancers beyond those associated with TEAD proteins are not well understood.…”

CD43 (sialophorin) is involved in the induction of extracellular matrix remodeling and angiogenesis by lung cancer cells

“…How CD43 achieves this remains to be established as, different to lymphoid cells, in NSCLC and SCLC cells, CD43 is exclusively an intracellular protein, present in the cytoplasm and the nucleus(Fu et al, 2013), probably performing different functions with different partners in either compartment. Interestingly, the Hippo pathway has been shown to participate in regulating genes associated with ECM organization and angiogenesis in NSCLC(Shreberk-Shaked et al, 2020). Whether this pathway is one of the mechanisms by which CD43 participates in remodeling the tumor microenvironment remains to be investigated.ACKNOWLEDGMENTSThis study is submitted in partial fulfillment of the requirements for the doctoral degree of the Programa de Maestría y Doctorado en Ciencias Bioquímicas-UNAM of Daniela Vega-Mendoza.…”

YAP and endothelin-1 signaling: an emerging alliance in cancer

“…Notably, growing evidence for YAP and TAZ different functions that are associated with diverging transcriptional programs is emerging [90]. For example, in lung cancer cells YAP is mainly responsible of the transcription of genes involved in tumor cell proliferation, whereas TAZ preferentially modulates genes implicated in ECM organization and cell migration [90], suggesting that YAP and TAZ may direct complementary oncogenic activities.…”

“…Taking into account that YAP and TAZ can orchestrate non overlapping transcriptional programs regulating cellular outcomes [90], future investigations are needed to uncover the different activities of YAP and TAZ downstream of GPCR, as ET-1R, including the oncogenic network with mutp53. Together these findings suggest that breaking this oncogenic cross-talk driven by ET-1/ET-1R axis might be exploited in rational and tolerable combination treatment strategies in the clinical setting.…”