The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

Dhont, Ludovic; Mascaux, Céline; Belayew, Alexandra

doi:10.1007/s00018-015-2060-6

Cited by 38 publications

(36 citation statements)

References 92 publications

(195 reference statements)

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“…The promoter of HLTF is methylated and silenced in a number of cancers. 29 Using methylation-specific PCR, cell lines were identified with a methylated HLTF promoter, which correlated with low HLTF protein expression, and HCQ sensitivity ( Fig. S5-6; Table S1).…”

Section: Hltf Modulates Sensitivity To Multiple Lysosomal Autophagy Imentioning

confidence: 99%

ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells

et al. 2017

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Lysosomal autophagy inhibitors (LAI) such as hydroxychloroquine (HCQ) have significant activity in a subset of cancer cell lines. LAIs are being evaluated in cancer clinical trials, but genetic determinants of sensitivity to LAIs are unknown, making it difficult to predict which tumors would be most susceptible. Here we characterize differentially expressed genes in HCQ-sensitive (-S) and -resistant (-R) cancer cells. Notably, expression of canonical macroautophagy/autophagy genes was not associated with sensitivity to HCQ. Expression patterns of ALDH1A1 (aldehyde dehydrogenase 1 family member A1) and HLTF (helicase like transcription factor) identified HCQ-S (ALDH1A1 HLTF; ALDH1A1 HLTF) and HCQ-R (ALDH1A1 HLTF) cells. ALDH1A1 overexpression was found to enhance LAI cell entry and cytotoxicity without directly affecting lysosome function or autophagic flux. Expression of HLTF allows repair of DNA damage caused by LAI-induced reactive oxygen species, leading to HCQ resistance. Sensitivity to HCQ is increased in cells where HLTF is silenced by promoter methylation. HLTF overexpression blunted the antitumor efficacy of chloroquine derivatives in vitro and in vivo. Analysis of tumor RNA sequencing data from >700 patients in the Cancer Genome Atlas identified cancers including colon cancer, renal cell carcinoma, and gastric cancers, that were enriched for the HCQ-S or HCQ-R signature. These results provide mechanistic insights into LAI efficacy, and guidance for LAI clinical development.

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Section: Hltf Modulates Sensitivity To Multiple Lysosomal Autophagy Imentioning

confidence: 99%

ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells

et al. 2017

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“…There is evidence to indicate that HLTF functions as a tumor suppressor mainly through two mechanisms: Promoter hypermethylation or alternative mRNA splicing (4). The results of the present study provide novel insight into the suppressive role of HLTF in CRC.…”

Section: Discussionmentioning

confidence: 57%

“…Evidence indicate that both HLTF and TGF-β signaling play a paradoxical role in cancer progression (4,11). Whether TGF-β-HLTF-SMAD signaling plays a similar role in CRC is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Helicase-like transcription factor (HLTF), which is a member of the SWItch/sucrose non-fermenting (SWI/SNF) family, has been reported to be associated with the prognosis of a number of types of cancer. However, the role of HLTF as a tumor suppressor or promoter remains controversial (4). Previous studies have reported that HLTF functions as a tumor suppressor in DNA repair, genome stability maintenance and gene transcription (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…However, the role of HLTF as a tumor suppressor or promoter remains controversial (4). Previous studies have reported that HLTF functions as a tumor suppressor in DNA repair, genome stability maintenance and gene transcription (4)(5)(6)(7). A recent study reported that a high HLTF expression protected cells against apoptosis by impairing the effects of lysosomal autophagy inhibitors (8).…”

Section: Introductionmentioning

confidence: 99%

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HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro

Liu

Zhou

et al. 2018

Int J Oncol

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Helicase-like transcription factor (HLTF) has been identified as a tumor suppressor gene. The hypermethylation of HTLF is frequently observed in various types of cancer, including colorectal cancer (CRC). However, the mechanisms through which HLTF suppresses CRC progression remain unclear. Thus, the aim of the present study was to explore the biological function of HLTF in CRC cells and the underlying mechanisms. CRC tissues and cells were used to detect the expression of HLTF. Wound-healing and Transwell assays were performed to assess the motility of CRC cells. The results revealed that HLTF expression was significantly associated with the differentiation status, invasion depth, lymph node metastasis and distant metastasis. A low HLTF expression was significantly associated with a poor survival. Furthermore, HTLF knockdown or ectopic overexpression significantly promoted or suppressed the motility of CRC cells, respectively. With regard to the underlying molecular mechanisms, the protein expression of HTLF was upregulated when the CRC cells were stimulated with transforming growth factor (TGF)-β, and HLTF upregulation induced an increase in SMAD4 and p-SMAD2/3 expression and a decrease in levels of the TGF-β/SMAD pathway downstream genes, Vimentin and zinc finger e-box binding homeobox 1 (ZEB1). On the whole, the findings of this study suggest that HLTF is negatively associated with the progression of CRC, and its overexpression suppresses the migration and invasion of CRC cells by targeting the TGF-β/SMAD pathway.

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CBX3 Downregulates HLTF to Activate PI3K/AKT Signaling Promoting Cholangiocarcinoma

Xie,

Liang,

Mao

et al. 2024

Advanced Biology

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Cholangiocarcinoma (CCA) is an aggressive cancer with poor response to chemotherapy or radiation, necessitating novel therapeutic approaches. Epigenetic regulation, which is reversible, plays a significant role in cancer progression. CBX3 (HP1γ), a key heterochromatin protein, regulates gene expression by interacting with histone H3 lysine 9 trimethyl (H3K9me3) markers. While CBX3 is linked to tumor progression in various cancers, its role in CCA remains unclear. This study reveals that CBX3 and H3K9me3 enrich the HLTF promoter, a gene involved in chromatin remodeling and DNA repair. HLTF is often inactivated by hypermethylation in other cancers, suggesting tumor‐suppressive properties. Depleting CBX3 in CCA cells elevates HLTF expression, reducing proliferation, while HLTF silencing reverses this effect. Furthermore, HLTF overexpression inhibits PI3K‐AKT signaling activated by CBX3. These findings suggest CBX3 promotes CCA progression by suppressing HLTF expression.

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The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

Cited by 38 publications

References 92 publications

ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells

ALDH1A1 and HLTF modulate the activity of lysosomal autophagy inhibitors in cancer cells

HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro

CBX3 Downregulates HLTF to Activate PI3K/AKT Signaling Promoting Cholangiocarcinoma

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