KLHL14 is a tumor suppressor downregulated in undifferentiated thyroid cancer

Our plain-English summary of KLHL14 is a tumor suppressor downregulated in undifferentiated thyroid cancer, by M. Esposito, A. Migliaccio, S.C. Credendino, et al (Cell Death Discovery, 2024).

The study

• Authors: M. Esposito, A. Migliaccio, S.C. Credendino, R. Maturi, N. Prevete, G. De Vita
• Journal: Cell Death Discovery
• Published: 2024;10(1):297
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

KLHL14 is a substrate-binding subunit of Cullin-RING ligase 3 ubiquitin ligase complex, highly enriched in thyroid since early embryonic development, together with its antisense RNA KLHL14-AS. We have previously demonstrated that Klhl14-AS is a competing endogenous RNA regulating several differentiation and survival factors in thyroid cancer, acting as tumor suppressor. Recently, also KLHL14 has been shown to function as tumor suppressor in diffuse large B-cell lymphoma and in malignant mesothelioma. Here we show that KLHL14 expression is strongly reduced in anaplastic thyroid cancer, the less differentiated and most aggressive type of thyroid neoplasia. Such reduction is reproduced in different in vivo and in vitro models of thyroid cancer, being invariably associated with loss of differentiation. When Klhl14 expression is rescued in thyroid transformed cells, it reduces the cell proliferation rate and increase the number of apoptotic cells. On the other side, Klhl14 loss of function in normal thyroid cells affects the expression of several regulatory as well as functional thyroid markers. All these findings suggest that KLHL14 could be considered as a novel tumor suppressor in thyroid cancer, by also revealing its physiological role in the maintenance of a fully differentiated and functional thyroid phenotype.

© 2024. The Author(s).

In plain English

This laboratory study examined the gene KLHL14 in thyroid cancer. It did not study asbestos, and it mentions mesothelioma only when describing other researchers' work. The authors analyzed two public gene-expression datasets of human thyroid tissue, a mouse model of BRAFV600E-driven thyroid cancer, and Ras-transformed rat thyroid cells (FRTL5). KLHL14 was significantly reduced in anaplastic thyroid cancer in both datasets. Its reduction in papillary thyroid cancer was not significant. Klhl14 was also markedly reduced in the mouse cancers and in the transformed cells. When Klhl14 was restored in transformed cells, fewer colonies formed than in control plates (97 vs. 204 on average). Fewer cells were dividing (about 13% vs. 24.41% BrdU-positive, Klhl14 clones vs. control clone). More cells showed DNA damage linked to cell death (7.93% vs. 0.28% TUNEL-positive, Klhl14 pool vs. control pool). Reducing Klhl14 in normal rat thyroid cells lowered several thyroid marker proteins. The authors concluded that KLHL14 is a possible novel tumor suppressor gene in thyroid cancer, and they said further studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining analysis of public human gene-expression datasets, a transgenic mouse model, and experiments in rat thyroid cell lines
• Who was studied: Human thyroid samples from two public datasets: GSE65144 (13 non-tumoral, 11 anaplastic thyroid cancer) and GSE33630 (45 non-tumoral, 12 anaplastic, 49 papillary thyroid cancer). Also Tg-rtTA; TetO/BRAFV600E mice (four per group) and FRTL5 rat thyroid cells, normal and Ras-transformed.
• Exposure: No asbestos exposure was studied. The experimental factors were cancer-gene activation (doxycycline-induced BRAFV600E in mice; oncogenic Ras in rat thyroid cells), restoring Klhl14 in transformed cells, and knocking Klhl14 down in normal cells.
• Main results:
  • In both public datasets, KLHL14 was significantly lower in anaplastic thyroid cancer than in normal tissue. Its lower level in papillary thyroid cancer was not significant.
  • Doxycycline-treated BRAFV600E mice had a severe decrease of Klhl14 in their induced thyroid cancers compared with control mice.
  • Ras-transformed FRTL5 cells showed a strong reduction of Klhl14 compared with the parental FRTL5 cells.
  • In the clonogenic assay, plates of Klhl14-transfected transformed cells had fewer colonies than control plates (97 vs. 204 on average).
  • About 13% of cells were BrdU-positive (dividing) in both Klhl14-expressing clones, versus 24.41% in the empty-vector control clone. In the pools the figures were 11.88% (Klhl14) vs. 22.41% (control).
  • TUNEL-positive cells (a sign of DNA fragmentation and cell death) were 6.14% in clone K14-2 and 2.88% in clone K14-17, versus 0.35% in the control clone. In the pools they were 7.93% (Klhl14) vs. 0.28% (control).
  • When Klhl14 was knocked down in normal FRTL5 rat thyroid cells, NIS protein was strongly reduced compared with control samples at 48 and 72 hours. FoxE1 and Pax8 proteins were also lower at 48 and 72 hours.
• The authors' conclusion: The authors concluded that their data indicate KLHL14 as a possible novel tumor suppressor gene in thyroid cancer.
• Limitations the authors state:
  • The authors state that further studies are needed to establish which of the observed effects are directly due to Klhl14 activity and which are mediated by its targets.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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