A 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.

Context-dependent roles of YAP/TAZ in stem cell fates and cancer

“…In ovarian cancer, ANGPTL4 is a direct target of TAZ but not YAP [ 131 ]. Intriguingly, in non-small cell lung cancer, their overall transcriptional programs have little overlap: YAP activates genes involved in cell cycle progression whereas TAZ activates genes critical for migration, resulting in differential sensitivity to chemotherapeutics [ 132 ]. Therefore, their unique transcriptional targets can have biologically significant consequences.…”

“…Importantly, their unique roles in cancer have clinical significance. YAP high cancer cell lines are sensitive to the chemotherapeutic paclitaxel, but TAZ high cell lines are not, and many other cancer drugs seem to affect the two groups differently [ 132 ]. Given these findings, future studies on YAP or TAZ in cancer should strive to consider both paralogs and avoid treating them as functionally redundant.…”

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises

“…The complex is then responsible for cell proliferation and transformation. Abnormal nuclear expression of YAP/TAZ proteins is associated with poor prognosis of different types of cancer [ 11 , 12 , 13 , 14 , 15 ]. In addition, YAP/TAZ can associate with other transcription factors leading to cell remodelling, proliferation, and invasion [ 16 ].…”

Combined control of the fibroblast contractile program by YAP and TAZ

“…Specific unique roles for YAP and TAZ in certain contexts may reflect cell-and tissue-specific preferential expression of one or the other or could relate to specific binding partners or unique upstream regulator pathways that confer differences in YAP and TAZ activation or function. For example, YAP and TAZ have some distinct transcriptional and functional roles in breast cancer epithelial cells (38), whereas YAP predominantly controls proliferation and TAZ migration in lung cancer epithelial cells (39).…”