The developmental regulator HAND1 inhibits gastric carcinogenesis through enhancing ER stress apoptosis via targeting CHOP and BAK which is augmented by cisplatin

Abstract

Epigenetic disruption of tumor suppressor genes, particularly aberrant CpG methylation, plays a crucial role in gastric cancer (GC) pathogenesis. Through CpG methylome and expression profiling, a developmental transcription factor -Hand-And-Neural-crest-Derivative-expressed 1 (HAND1), was identified methylated and downregulated in GC. However, its role and underlying mechanisms in GC progression are poorly understood. Here, we show that HAND1 was frequently downregulated in GC by promoter methylation, and significantly correlated with tumor progression and poor prognosis of GC patients. High expression of HAND1 in GC patients was associated with significantly higher 5-year overall survival rates. Ectopic expression of HAND1 inhibited GC cell growth and migration in vitro and in vivo. HAND1 expression increased ROS levels and cytosolic Ca 2+ concentration, enhanced cisplatin-induced apoptosis through endoplasmic reticulum (ER) stress/mitochondria-mediated apoptosis. Knockdown of CHOP and BAK attenuated HAND1-induced cell apoptosis. Overexpression of CHOP increased BAK expression. HAND1 interacts with CHOP, also directly binds to CHOP and BAK promoters and positively regulates BAK transcription. Thus, the present study demonstrates that HAND1 is a tumor suppressor gene methylated in GC, induces ER stress and apoptosis via CHOP and BAK, which is augmented by cisplatin. Low HAND1 expression is an independent poor prognostic factor for GC. The tumor-specific methylation of HAND1 promoter could be a candidate biomarker for GC.

Circulating-tumour DNA methylation of HAND1 gene: a promising biomarker in early detection of colorectal cancer

“…Our study revealed that the methylation levels of the HAND1 CpG site in CRC patients demonstrated a sensitivity of 93.33% (95% CI, 70.18–99.66%) and a specificity of 80.00% (95% CI, 62.69–90.49%), with a cut-off value greater than 1.57. It has been demonstrated that the expression of HAND1 is controlled by the promoter region, which is regulated by cytosine methylation [ 8 ]. HAND1 /2 proteins are essential in heart development, promoting cell proliferation and differentiation alongside other transcription factors like Nkx2-5 and GATA4.…”

“…It is crucial to comprehend the multifaceted roles of these transcription factors in normal heart development and tumour formation [ 22 ]. Furthermore, studies demonstrated that the HAND1 gene was hypermethylated and downregulated in gastric cancer [ 8 ] and is believed to function as a tumour suppressor gene. These findings suggest that HAND1 gene methylation status may be a potential diagnostic biomarker for CRC patients.…”

“…Its involvement in cell proliferation and differentiation of trophoblast and cardiomyocytes has been well-documented [ 7 ]. In several types of cancer, including colorectal, pancreatic, small cell lung, ovarian, thyroid, and melanoma, HAND1 is downregulated and methylated [ 8 ]. This gene, epigenetically silenced in colon cancer, has been identified as a Polycomb target closely associated with ES cell differentiation.…”

The dual effect of endoplasmic reticulum stress in digestive system tumors and intervention of Chinese botanical drug extracts: a review

“…Zhou Y et al (2021) reported that long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) significantly upregulated ERS-related proteins (XBP-1s/XBP-1U and GRP78) and apoptosis-related proteins (Bax and cleaved Caspase-3), inhibited GC cell proliferation and invasion, and promoted apoptosis. Both vivo and vitro experiments showed that the transcription factor hand and neural crest derivative expressed 1 (HAND1) upregulated expression of BIP, CHOP, ATF6, PERK, ATF4, XBP1-s and IRE1α and synergized with cisplatin in inducing GC cell lines AGS and MKN-28 apoptosis, and knockdown of CHOP attenuated this effect ( Kuang Y et al, 2023 ). Another study showed that silencing the key Calnexin gene in ERAD was able to induce SGC-7901 apoptosis accompanied by an increase in the expression levels of ERS-associated GRP94, IRE1, ATF6, and CHOP proteins ( Zhang, XH et al, 2017 ).…”

Identification of a novel apoptosis-related genes signature to improve gastric cancer prognosis prediction

“…Anti-apoptotic molecules, such as Bcl-2, are frequently upregulated in cancer cells that are resistant to drug treatments [ 6 ]. The expression of BAK, a member of the Bcl-2 family, can predict chemotherapeutic responses to docetaxel in patients with GC and is an effective prognostic biomarker [ 7 ]. Recently, a growing number of genes are being recognized as biomarkers for GC, which contribute to improving the outcomes of patients with this disease.…”